Skip to main content
NCBI home page
Journal of Zhejiang University (Medical Sciences) logoLink to Journal of Zhejiang University (Medical Sciences)
. 2020 Feb 25;49(1):58–70. [Article in Chinese] doi: 10.3785/j.issn.1008-9292.2020.02.25

铁稳态代谢表观遗传调控机制的研究进展

Progress on epigenetic regulation of iron homeostasis

Lingyan DUAN 1, Xiangju YIN 2, Hong'en MENG 1, Xuexian FANG 1, Junxia MIN 1, Fudi WANG 1,*
PMCID: PMC8800797  PMID: 32621410

Abstract

Iron homeostasis plays an important role for the maintenance of human health. It is known that iron metabolism is tightly regulated by several key genes, including divalent metal transport-1( DMT1), transferrin receptor 1( TFR1), transferrin receptor 2( TFR2), ferroportin( FPN), hepcidin( HAMP), hemojuvelin( HJV) and Ferritin H. Recently, it is reported that DNA methylation, histone acetylation, and microRNA (miRNA) epigenetically regulated iron homeostasis. Among these epigenetic regulators, DNA hypermethylation of the promoter region of FPN, TFR2, HAMP, HJV and bone morphogenetic protein 6 ( BMP6) genes result in inhibitory effect on the expression of these iron-related gene. In addition, histone deacetylase (HADC) suppresses HAMP gene expression. On the contrary, HADC inhibitor upregulates HAMP gene expression. Additional reports showed that miRNA can also modulate iron absorption, transport, storage and utilization via downregulation of DMT1, FPN, TFR1, TFR2, Ferritin H and other genes. It is noteworthy that some key epigenetic regulatory enzymes, such as DNA demethylase TET2 and histone lysine demethylase JmjC KDMs, require iron for the enzymatic activities. In this review, we summarize the recent progress of DNA methylation, histone acetylation and miRNA in regulating iron metabolism and also discuss the future research directions.

Keywords: Iron/metabolism, DNA methylation, Histones/protein modification, MicroRNAs, Epigenetics, Review

铁是人体必需的微量元素，不仅参与血红素合成，而且作为一些关键酶的辅基在多种生理代谢中发挥重要功能 [ 1] 。铁缺乏可引发缺铁性贫血 [ 2] 。人类遗传性血色病是一类由基因突变引起的铁过载疾病 [ 3] ，导致多个器官中铁积累，皮肤色素沉积及多种器官的病变，如2型糖尿病 [ 4] 、肝纤维化 [ 5] 等。超过85 %血色病患者携带遗传性血色素沉着病蛋白(hemochromatosis protein, HFE)突变基因 [ 6] ，少数患者携带铁调素(hepcidin, HAMP) [ 7] 、铁调素调节蛋白(hemojuvelin, HJV) [ 8] 、铁外排蛋白(ferroportin 1, FPN) [ 9] 或转铁蛋白受体(transferrin receptor, TFR )2 [ 10] 突变基因，近期有报道成纤维细胞生长因子6基因突变引发血色病及影响铁稳态代谢 [ 11] 。铁过载可增加肿瘤、糖尿病、神经退行性变性疾病和心血管疾病等发病风险 [ 12] ，还可引起一种铁依赖的新型细胞死亡方式——铁死亡 [ 13] 。笔者团队在2017年和2019年先后发现铁稳态失衡可诱发铁死亡介导的肝脏及心脏器官损伤 [ 14- 15] 。铁稳态失衡导致的疾病不仅是营养学问题，更是医学问题，研究铁稳态代谢的调控机制有望为治疗相关疾病提供依据。

机体主要由铁的吸收、利用、储存及循环等环节精密协作，通过调节肠内铁的吸收和网状内皮系统细胞中铁的循环，严格维持系统内铁稳态。铁稳态的维持是一个复杂而精密的体系和过程，涉及多个环节、多种蛋白(基因)。细胞铁稳态代谢主要受铁调节蛋白(iron regulatory protein, IRP)-铁反应元件的调控 [ 16] ，其中IRP可调节铁的吸收、转运和储存相关蛋白的表达，如TFR1、二价金属离子转运蛋白(divalent metal transport 1, DMT1)和铁蛋白等，见 图 1。机体系统铁代谢主要受HAMP-FPN的调控 [ 17] ，其中HAMP是组织中铁摄取和释放的关键调节剂，是全身铁稳态的控制中心。铁过载时，HAMP能与靶细胞膜上的FPN结合，并在溶酶体中使FPN内化和降解，从而抑制肠细胞对铁的吸收以及巨噬细胞或肝细胞向血清中释放铁，调节铁的吸收和分布 [ 18] 。在分子水平上，HAMP受骨形态生成蛋白(bone morphogenetic protein, BMP)/HJV/SMAD信号通路的调节 [ 19- 20] 。HJV是BMP的共受体；通过增强BMP表达，刺激SMAD信号通路，促进 HAMP的表达 [ 19, 21] 。BMP刺激 HAMP表达这一过程也受HFE蛋白的调控 [ 22] 。在高铁环境中，转铁蛋白竞争性夺取与HFE结合的TFR1，导致HFE与TFR1分离，而与TFR2结合，从而激活SMAD信号通路，诱导 HAMP的表达 [ 23] 。膜型丝氨酸蛋白酶2(matriptase-2，又称TMPRSS6)通过剪切HJV负反馈抑制 HAMP的表达 [ 24] 。HAMP调控信号转导通路中任何基因异常都将影响 HAMP的表达，引起机体出现铁代谢紊乱相关疾病。近年来，随着铁代谢机制研究的不断深入，越来越多的研究成果显示表观遗传在铁稳态代谢中发挥的重要作用。本文综述了DNA甲基化、组蛋白修饰和非编码RNA调控铁稳态代谢的研究进展。

图1.

铁稳态代谢和表观遗传调控铁代谢

膳食铁主要通过位于小肠上部的铁外排蛋白(FPN)吸收入体内，转铁蛋白受体1是转铁蛋白(Tf)结合铁进入几乎所有类型细胞的门户，细胞内多余的铁储存在铁蛋白中.其中，细胞内铁稳态受铁调节蛋白-铁反应元件的调节，系统性铁稳态受铁调素-FPN轴的调控.表观遗传调控蛋白如DNA去甲基酶TET基因家族成员2(TET2)可促进FPN的表达，组蛋白乙酰转移酶2A(KAT2A)、甲基化CpG结合域蛋白5(MBD5)和组蛋白脱乙酰酶(HDAC)抑制剂可促进铁蛋白的表达，而微RNA可抑制二价金属离子转运蛋白( DMT1 )、 FPN、铁蛋白、铁调节蛋白等铁代谢相关基因的表达，参与铁稳态代谢.实线箭头代表激活，T型线代表抑制，虚线箭头代表间接作用.Dcytb：十二指肠细胞色素b；HMOX1:血红素加氧酶1；Steap:前列腺六跨膜上皮抗原.

图1

Open in a new tab

1 铁稳态代谢与DNA甲基化调控

DNA甲基化一般发生在胞嘧啶-鸟嘌呤二核苷酸CpG丰富区域，亦称为CpG岛，是研究最广泛的表观遗传修饰，在基因表达调控中发挥重要作用。DNA甲基化增加可导致基因沉默，甲基化减少则会激活基因表达 [ 25] 。铁代谢与DNA甲基化密切相关，铁水平和状态可影响DNA甲基化 [ 26] 。 Hfe突变小鼠引起脑中游离铁含量升高，发生氧化应激导致产生过多的S-腺苷同型半胱氨酸，后者通过抑制DNA甲基转移酶的活性抑制DNA甲基化 [ 27] ，用铁螯合剂去铁胺处理可以提高DNA甲基转移酶的活性并能诱导一些乳腺癌细胞的超甲基化 [ 28] 。3-羟基丁酸脱氢酶2是哺乳动物嗜铁素合成的限速酶 [ 29] ，抑制其表达可引起细胞和线粒体内铁过载 [ 29- 30] 。研究发现，抑制3-羟基丁酸脱氢酶2表达可增加系统性红斑狼疮患者中CD4 + T细胞内的铁含量而导致DNA高羟甲基化和低甲基化 [ 31] ，从而导致免疫相关基因 CD70 、 CD11A 和 CD40L 的过度表达及T细胞的自我激活 [ 32- 36] 。

DNA复制过程中，当出现DNA甲基转移酶功能受损、辅助因子S-腺苷甲硫氨酸不足时，DNA甲基化将被抑制，5-甲基胞嘧啶残基丢失或被氧化为未甲基化的胞嘧啶，导致DNA被动去甲基化 [ 37] 。近年研究发现，DNA去甲基化主要由TET(ten-eleven translocation)调控，TET通过氧化甲基化胞嘧啶以促进DNA去甲基化 [ 38] 。TET家族属于二价铁离子和2-酮戊二酸依赖型双加氧酶家族，缺铁会导致TET活性下降，减少5-甲基胞嘧啶向5-羟基胞嘧啶的转化 [ 39] 。TET2作为DNA去甲基化酶，可增加启动子CpG岛的基因转录活性，促进基因表达。研究发现TET2在铁稳态代谢调控中发挥了重要作用。TET2缺乏可导致人和动物红细胞生成紊乱 [ 40] ，动物实验也证实，敲降 TET2 基因或减少 TET2 表达可引起铁蓄积和轻度贫血，主要通过影响线粒体铁代谢和血红素生物合成相关基因(如 Fech、 Abcb7 和 Sf3b1 )CpG位点的甲基化，抑制其表达，导致线粒体铁水平及血清、线粒体铁蛋白升高 [ 41] 。氧化应激可影响机体造血红细胞生成，导致机体对铁的需求量增加，造成铁稳态和HAMP-FPN轴失衡，同时引起5-羟基胞嘧啶和TET2表达升高。研究发现，TET2可通过去甲基化 FPN和 Erythroferrone启动子区促进其表达从而对抗氧化应激 [ 42] ; 也可以通过去甲基化核转录因子E2相关因子2(nuclear factor erythroid 2 related factor 2, Nrf2 )增加其表达，从而促进 FPN和 Erythroferrone的表达，应对造血压力 [ 42] 。可见TET2在造血方面对铁稳态代谢的调控发挥了重要作用。

肿瘤增殖过程中往往对铁的需求明显增加，同时影响铁代谢相关基因的表达。研究发现，乳腺癌患者中 FPN低表达提示低生存率 [ 43] 。体外研究也发现，抑制 FPN的表达可促进肿瘤生长，而过表达 FPN可阻碍肿瘤生长 [ 43] 。乳腺癌中 FPN低表达一方面受 Nrf2 和髓系锌指1低表达的调控，另一方面因 FPN启动子区域CpG岛发生高甲基化，导致其表达受到抑制 [ 44] ，这预示着可通过靶向 FPN或上游调控因素来抑制乳腺癌。肿瘤基因组图谱(TCGA)数据库中12种肿瘤的甲基化数据显示， TFR2 异常表达与其受启动子区的甲基化异常有关 [ 45] 。肝癌患者中 HAMP表达受到抑制伴随其启动子区高度保守的CpG岛位点的高甲基化 [ 46] ；肝癌细胞经去甲基化药物处理可去除 HAMP启动子的高甲基化，上调 HAMP的表达，肝癌细胞中 TFR2 也受到同样的调控 [ 47] 。因此，高甲基化调控 HAMP是表观遗传调控铁代谢的一个新发现，为铁与肿瘤之间相关研究开辟了新的前景。研究还发现，大鼠经减肥手术后 Hamp启动子区DNA甲基化水平明显高于假手术组，导致 Hamp表达降低，改善大鼠减肥手术后的缺铁症状 [ 48] 。骨髓增生异常综合征患者 HJV启动子区CpG岛的甲基化可抑制该基因表达，去甲基化药物可提高 HJV的表达，且能够明显改善患者因重复输血导致的铁蓄积 [ 49] 。肝癌患者肝脏组织 BMP6 的启动子区CpG岛发生高度甲基化，导致 BMP6 低表达，且低于癌旁组织 [ 50] ，这与患者预后不良有关，提示BMP6可作为预后的一个指标。可见，铁代谢表观遗传机制中存在多个可能的肿瘤防控靶点。

2 铁稳态代谢与组蛋白修饰调控

组蛋白是染色体基本单位核小体的重要组成部分。核小体是由约147对碱基缠绕两份核心组蛋白(H2A、H2B、H3和H4)组成的八聚体 [ 51- 52] 。组蛋白修饰主要包括甲基化、乙酰化、磷酸化及泛素化修饰，染色体经组蛋白修饰后可调控基因表达 [ 53] 。甲基化和乙酰化是组蛋白修饰中最丰富、最广泛的修饰方式，参与调控铁稳态代谢。

2.1 铁稳态代谢与组蛋白乙酰化调控

组蛋白乙酰化是一种可逆的翻译后修饰，在调控真核基因表达和染色质结构及功能方面起着重要作用。组蛋白乙酰化修饰受组蛋白乙酰转移酶和组蛋白脱乙酰酶(histone deacetylase, HDAC)的动态拮抗调控 [ 54- 55] 。一般而言，乙酰化激活基因表达，而去乙酰化抑制基因的表达。铁和组蛋白乙酰化可相互影响，一方面铁过载可抑制组蛋白乙酰化，另一方面多个研究表明乙酰化可调控铁代谢。脑中铁蓄积会造成海马区H3K9乙酰化水平降低，从而导致记忆障碍，引起神经退行性疾病的发生 [ 56] 。而给铁过载小鼠注射HADC抑制剂丁酸钠即可缓解铁过载引起的记忆障碍 [ 56] 。 Hfe或 Hjv敲除小鼠为铁过载模型，其视网膜上皮细胞迁移增加，葡萄糖摄取增加，HDAC和DNA甲基转移酶的表达水平均增加，这些表征促进视网膜色素上皮细胞增殖 [ 57] 。在脑缺血损伤导致凋亡发生的过程中，无铁反应元件的DMT1 1B亚型[1B/(-)IRE DMT1]是核因子NF-κB/RelA在Lys310位点激活和乙酰化的早期靶点，抑制1B/(-)IRE DMT1表达或降低NF-κB/RelA在Lys310位点的乙酰化水平，可抑制铁的吸收，缓解脑缺血引起的神经损伤 [ 58] 。一些HDAC抑制剂可上调铁蛋白重链表达，在不改变其乙酰化水平的情况下，促进转录因子Sp1与其启动子区核因子NF-Y结合，从而诱导铁蛋白重链的表达 [ 59] ，表明HDAC抑制剂可作为维持细胞内铁稳态的潜在药物。另有研究发现，甲基CpG结合结构域蛋白5(methyl-CpG-binding domain 5, MBD5)在组蛋白乙酰转移酶2A(KAT2A)的作用下诱导小肠内铁蛋白重链乙酰化，促进铁蛋白重链的表达，调节小肠储存铁 [ 60] ，维持铁稳态。SIRT2是一种存在于细胞质的脱乙酰酶，可结合Nrf2使其去乙酰化，导致 FPN表达减少，进而阻止细胞内铁的排出 [ 61] 。可见，多种组蛋白乙酰化相关蛋白在铁稳态代谢中发挥重要作用。

HAMP在铁稳态代谢中发挥至关重要的作用，因此研究者逐渐把铁稳态代谢的组蛋白乙酰化调控聚焦在HAMP上( 图 2)。 HAMP的表达受其启动子区组蛋白乙酰化水平调控。体外过表达SMAD4可导致 HAMP启动子区组蛋白H3K9乙酰化升高，提高 HAMP启动子区的活性，上调 HAMP基因的表达 [ 62] ，调控机体铁稳态。丙型肝炎病毒可引起 HAMP组蛋白去乙酰化，下调 HAMP，促进铁的吸收，从而抑制HAMP的抗病毒作用 [ 63] 。研究报道，丙型肝炎病毒可诱使肝癌细胞产生活性氧，激活HDAC的活性，抑制CCAAT/增强子结合蛋白α(CCAAT/enhancer-binding protein α, C/EBPα)及信号传导蛋白和转录激活物(signal transducers and activators of transcription 3, STAT3)与 HAMP启动子的结合，进而抑制 HAMP的表达，促进病毒复制；而HDAC抑制剂可促进 HAMP组蛋白乙酰化，恢复C/EBPα和STAT3与 HAMP启动子的结合，抑制病毒复制 [ 64] 。缺铁或红细胞增多小鼠的HADC3可与 Hamp基因位点的染色质结合降低其乙酰化水平，抑制 Hamp表达，而HDAC3抑制剂可增加 Hamp的表达 [ 65] 。另有研究发现，HDAC抑制剂可增加肝癌细胞系HepG2细胞中 HAMP的表达 [ 66- 67] 。可见HDAC抑制剂可通过提高 HAMP启动子区的乙酰化水平从而调控铁代谢。笔者团队证实，HDAC1调控 Hamp不是通过调节 Hamp启动子区组蛋白去乙酰化，而是直接与SMAD4结合，抑制SMAD4与 Hamp启动子区域的结合，进而抑制 Hamp的表达，并确定了HADC1抑制剂在体内外均可有效减轻铁蓄积症状，在治疗铁过载疾病中具有潜在的应用前景 [ 68] 。以上研究表明，HAMP可作为表观遗传调控靶点治疗铁稳态代谢失衡疾病。

图2.

铁调素的表观遗传调控

铁调素是肝细胞分泌的成熟激素肽，由BMP/SMAD信号通路调控，是维持铁稳态的关键因子.表观遗传调控蛋白如组蛋白脱乙酰酶家族成员1和3(HADC1、HADC3)和微RNA可抑制铁调素及其相关基因如转铁蛋白受体( TFR)1 、 TFR2 、遗传性血色素沉着病蛋白( HFE)、铁调素调节蛋白( HJV)的表达，而去甲基化药物和组蛋白脱乙酰酶(HADC)抑制剂可上调铁调素和HJV的表达, 参与铁代谢.Tf:转铁蛋白；BMP6：骨形态生成蛋白BMP家族成员6；Tmprss6：膜型丝氨酸蛋白酶2；SMAD4/SMAD7：SMAD蛋白家族成员4和7；P：磷酸化.

图2

Open in a new tab

2.2 铁稳态代谢与组蛋白甲基化调控

组蛋白甲基化状态受组蛋白赖氨酸特异性去甲基化酶(lysine specific demethylase，LSD, 也称KDM)的调控，KDM主要包括KDM1亚家族(KDM1A也称LSD1，KDM1B也称LSD2)和含JumonjiC结构域组蛋白去甲基化酶(JmjC KDM)家族(KDM2-7) [ 69] 。其中JmjC KDM家族为二价铁离子和2-酮戊二酸依赖型双加氧酶家族 [ 70] ，铁的水平和状态可影响JmjC KDM家族去甲基化酶的活性，调控基因的表达。

SMAD4过表达可引起 HAMP启动子区域H3K4甲基化增加，提高 HAMP的表达 [ 62] 。LSD1是组蛋白H3K4和H3K9的去甲基化酶，可去甲基化为单一或二甲基赖氨酸 [ 71- 72] 。CHBH是一种LSD1抑制剂 [ 73] ，可作用于肿瘤细胞，提高组蛋白H3甲基化水平，降低组蛋白H3乙酰化水平，同时螯合细胞中的铁发挥抗肿瘤作用 [ 74] 。去铁胺是JmjC KDM的抑制剂 [ 75] 。Sarno等 [ 76] 首次证实铁螯合剂去铁胺可通过升高结直肠癌细胞组蛋白甲基化水平，使多种细胞生长和增殖基因表达下降，从而抑制结直肠癌细胞增殖。笔者团队发现，铁缺乏可导致依赖2-酮戊二酸和二价铁离子的KDM2B、KDM3B和KDM4C酶活性降低，抑制H3K9去甲基化，进而抑制细胞周期蛋白E1启动子激活和B细胞增殖，抗体产生下降，从而使得铁缺乏机体对麻疹疫苗反应性降低 [ 77] ，可见铁代谢、组蛋白甲基化及生理功能存在密切关联。

3 铁稳态代谢与微RNA调控

微RNA(miRNA)是非编码RNA中最大的亚类，是真核细胞中最丰富的一类基因调控分子，调节绝大部分蛋白质编码基因 [ 78] 。miRNA通过与靶基因mRNA的3′UTR非翻译区的互补序列结合负调控基因表达，抑制mRNA翻译或诱导其降解 [ 79- 80] ，在细胞内多种生物学过程和疾病过程中发挥重要作用。miRNA是铁稳态代谢的重要调控因子，可通过调控铁吸收、转运、储存和利用等多个过程维持铁稳态。miRNA调控铁代谢相关靶点基因如 表 1所示。

表1 微RNA调控铁代谢的关键靶点

Table 1 Known miRNA regulate iron-related genes

靶点

微RNA

文献

二价金属离子转运蛋白

miR-let-7d、miR-16家族

[ 81- 82]

铁外排蛋白

miR-20a、miR-20b、miR-485-3p

[ 83- 85]

转铁蛋白受体1

miR-210、miR-320、miR-152、miR-148a、miR-7-5p、miR-141-3p

[ 86- 90]

铁硫簇组装蛋白

miR-210

[ 91]

转铁蛋白受体2

miR-221

[ 92]

核转录因子E2相关因子2

miR-144

[ 93]

铁蛋白重链

miR-200b

[ 94]

铁反应元件结合蛋白2

miR-29家族

[ 95]

骨形态生成蛋白Ⅰ型受体

miR-130a

[ 96]

铁调素调节蛋白

miR-122

[ 97]

血色素沉着病蛋白

miR-122

[ 97]

5-氨基酮戊酸合成酶

miR-218

[ 98]

γ-珠蛋白

miR-96

[ 99]

Bach 1(一种编码血红素调节转录抑制因子的基因)

miR-let-7、miR-196、miR-27a-5p

[ 100- 102]

乳铁蛋白

miR-214

[ 103]

乳铁蛋白受体

miR-584

[ 104]

Open in a new tab

3.1 miRNA调控铁吸收和铁转运

在红系分化中，miR-let-7d过表达可降低CD34 +造血祖细胞、K562细胞和HEL细胞中无铁反应元件 DMT1 的mRNA和蛋白水平，抑制铁输出，导致铁在内吞体中蓄积，从而抑制红系分化 [ 81] ，对造血产生一定影响。miR-16家族(miR-16、miR-195、miR-497和miR-15b)在体内外均能抑制肠道 DMT1 的表达，抑制铁的吸收 [ 82] 。FPN是哺乳动物细胞中唯一已知的铁外排通道，肺癌患者中miR-20a表达增加可抑制 FPN表达，导致细胞内铁滞留，促进肿瘤增殖 [ 83] 。同时，miR-20b在体内外均能调节小肠 FPN的表达，为肠道铁吸收提供了一个潜在靶点 [ 84] 。缺铁可诱导miR-485-3p产生，后者可直接作用于肿瘤细胞中 FPN的3′UTR进而抑制其表达，减少肿瘤细胞内铁的排出 [ 85] 。过表达miR-485-3p不仅抑制了 FPN的表达，还引起细胞内铁蛋白水平的增加，调控细胞内铁稳态 [ 85] 。

缺铁或缺氧可诱导miR-210表达，而miR-210过表达可下调 TFR1 ，抑制铁的转运和吸收 [ 86] 。同时低氧诱导的miR-210也可通过调节铁硫簇(Fe-S)组装蛋白(ISCU1/2)表达来抑制铁硫簇的发生和组装 [ 91] 。TFR1在大多数恶性肿瘤中表达增加 [ 105] 。miR-320靶向 TFR1 可抑制其表达，进而抑制急性髓系白血病细胞的增殖 [ 87] 。肝癌细胞中miR-152和miR-148a特异性靶向 TFR1 ，抑制其表达可能为肝癌提供一种选择性的抗肿瘤治疗方法 [ 88- 89] 。同时miR-7-5p和miR-141-3p下调 TFR1 也有同样的抗肿瘤作用 [ 90] 。可见多种miRNA可通过下调 TFR1 表达进而抑制铁的吸收和转运，达到抑制肿瘤增殖的作用。SH-SY5Y细胞过表达miR-221可抑制 TFR2 的表达，因此抑制内源性的miR-221可上调 TFR2 [ 92] 。miR-144在严重贫血中高表达，上调miR-144的表达可导致 Nrf2 的表达降低，尤其是在地中海贫血中 [ 93] 。

3.2 miRNA调控铁储存

miRNA调节细胞铁稳态。铁蛋白可调节原癌基因 MYC和抑癌基因 p53 表达，在肿瘤发生中发挥作用 [ 106- 107] 。在乳腺癌MDA-MB-231细胞中，过表达miR-200b可抑制铁蛋白重链表达，从而抑制铁储存 [ 94] 。在鱼类、小鼠、灵长类(猴)和人类等不同脊椎动物的正常老化过程中miR-29家族成员(miR-29a、miR-29b和miR-29c)均被上调 [ 108- 110] 。Ripa等 [ 95] 发现编码IRP2蛋白的铁反应元件结合蛋白2( irbe2 )是miR-29的靶点，铁离子可诱导miR-29表达，从而降低 irbe2 的表达。另外，miR-29神经系统特异突变鱼表现出 irp2 和 Tfr1 表达升高，铁含量增加，氧化应激增加 [ 95] 。因此miRNA提供了调控细胞内铁稳态的新机制。

miRNA亦可调节机体系统铁稳态。如缺铁小鼠可诱导miR-130a表达，靶向 Bmp的Ⅰ型受体ALK2，减少BMP/SMAD信号，抑制Hamp的合成，提高铁的吸收 [ 96] 。miR-122是在肝脏特异性高表达的miRNA [ 111- 112] ，其耗竭直接刺激肝组织和小鼠肝原代细胞中 Hfe、 Hjv和小鼠的 Bmp 1A型受体转录增加，导致 Hamp mRNA水平升高，引起小鼠全身铁缺乏，血浆和肝铁下降，造血受损，脾外红细胞生成增加 [ 97] 。

3.3 miRNA调控铁利用

5-氨基酮戊酸合成酶(5-aminolevulinate synthase 2, ALAS2)是一种编码血红素合成的关键酶，对血红素合成和红细胞功能至关重要。ALAS2还可通过与IRP结合来参与铁代谢 [ 113] 。miR-218通过靶向调控 ALAS2 ，抑制红系分化，从而导致铁代谢的改变 [ 98] 。铁在机体中的主要作用就是参与红细胞生成，而许多miRNA在红细胞生成的最初阶段高度表达，却在正常红细胞增殖(miR-223)、分化(miR-150)和成熟(miR-221/222)过程中表达下降 [ 114] 。miR-96在成人网织红细胞高度表达，通过直接与γ-珠蛋白相互作用并抑制其表达调节红细胞生成 [ 99] 。在肝细胞中，过表达miR-let-7可直接作用于 Bach 1 (一种编码血红素调节转录抑制因子的基因)mRNA的3′UTR非翻译区，从而抑制该蛋白的表达，并上调血红素加氧酶1的表达，减轻肝细胞的氧化损伤 [ 100] 。有研究发现，miR-196和miR-27a-5p可降低 Bach1 mRNA，抑制丙型肝炎病毒的复制或减轻小鼠肝脏缺血再灌注导致的凋亡 [ 101- 102] 。乳腺上皮细胞中miR-214过表达可抑制乳铁蛋白的表达 [ 103] 。Liao等 [ 104] 还观察到人肠上皮细胞株(Caco-2)和小鼠小肠中miR-584可调控乳铁蛋白受体转录。

4 结语

铁是生物体生长发育及新陈代谢过程中必不可少的微量元素。铁稳态代谢受到众多基因的精密调控，相关基因表达出现异常可导致机体铁稳态失衡。随着铁代谢的表观遗传机制研究的不断深入，DNA甲基化、组蛋白修饰和miRNA在铁稳态代谢中都取得了诸多令人振奋的进展，极大地丰富了我们对铁代谢理论的理解，为靶向铁代谢的疾病防控提供了系列新靶点。

目前表观遗传药物研究取得重大成果，已有多种靶向表观遗传的药物获得监管部门批准而应用于临床，如DNA甲基化转移酶抑制剂和HDAC抑制剂被批准用于血液系统恶性肿瘤的临床治疗，为利用表观遗传机制治疗疾病提供科学依据 [ 115- 116] 。如前文所述，目前已筛选出一些表观遗传抑制剂如去甲基化药物和一些HADC抑制剂可上调HJV和HAMP的表达。这些成果为从表观遗传角度研究铁代谢和治疗铁稳态失衡疾病提供了研究基础和指引了重要方向，期待表观遗传药物成为治疗铁稳态失衡疾病的重要策略。

虽然DNA甲基化、组蛋白修饰和miRNA在铁代谢方面已经取得很多进展，但铁稳态代谢的表观遗传分子机制仍有待更加深入的研究。DNA甲基化调控铁代谢研究主要集中在肿瘤方面，缺少更多其他疾病模型，尤其是铁稳态失衡疾病如地中海贫血和血色病等；组蛋白修饰中组蛋白甲基化调控铁代谢研究还不够全面，缺少更多动物和临床实验性研究，这既是缺陷又有很大的研究前景，可探究组蛋白甲基化是如何调控铁代谢的；虽然miRNA调控铁代谢的研究不少，但miRNA在临床上的应用较少。目前铁稳态代谢以HAMP-FPN轴调控网络研究较为全面，可运用CRISPR/Cas9与Cre-loxp技术、蛋白质组学、代谢组学以及测序技术等现代生物技术，针对铁稳态代谢的不同基因、不同阶段全面探究表观遗传调控铁代谢的具体机制。

Funding Statement

国家重点研发计划(2018YFA0507800);国家自然科学基金(31930057, 31530034, 31570791)

References

  • 1.HENTZE M W, MUCKENTHALER M U, ANDREWS N C. Balancing acts:molecular control of mammalian iron metabolism. Cell. 2004;117(3):285–297. doi: 10.1016/s0092-8674(04)00343-5. [HENTZE M W, MUCKENTHALER M U, ANDREWS N C. Balancing acts:molecular control of mammalian iron metabolism[J]. Cell, 2004, 117(3):285-297. DOI:10.1016/s0092-8674(04)00343-5.] [DOI] [PubMed] [Google Scholar]
  • 2.MCLEAN E, COGSWELL M, EGLI I, et al. Worldwide prevalence of anaemia, WHO vitamin and mineral nutrition information system, 1993-2005. Public Health Nutr. 2009;12(4):444–454. doi: 10.1017/S1368980008002401. [MCLEAN E, COGSWELL M, EGLI I, et al. Worldwide prevalence of anaemia, WHO vitamin and mineral nutrition information system, 1993-2005[J]. Public Health Nutr, 2009, 12(4):444-454. DOI:10.1017/S1368980008002401.] [DOI] [PubMed] [Google Scholar]
  • 3.PIETRANGELO A. Hereditary hemochromatosis-a new look at an old disease. N Engl J Med. 2004;350(23):2383–2397. doi: 10.1056/NEJMra031573. [PIETRANGELO A. Hereditary hemochromatosis-a new look at an old disease[J]. N Engl J Med, 2004, 350(23):2383-2397. DOI:10.1056/NEJMra031573.] [DOI] [PubMed] [Google Scholar]
  • 4.FERNÁNDEZ-REAL J M, LÓPEZ-BERMEJO A, RICART W. Cross-talk between iron metabolism and diabetes. Diabetes. 2002;51(8):2348–2354. doi: 10.2337/diabetes.51.8.2348. [FERNÁNDEZ-REAL J M, LÓPEZ-BERMEJO A, RICART W. Cross-talk between iron metabolism and diabetes[J]. Diabetes, 2002, 51(8):2348-2354. DOI:10.2337/diabetes.51.8.2348.] [DOI] [PubMed] [Google Scholar]
  • 5.GUYADER D, JACQUELINET C, MOIRAND R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis. Gastroenterology. 1998;115(4):929–936. doi: 10.1016/s0016-5085(98)70265-3. [GUYADER D, JACQUELINET C, MOIRAND R, et al. Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis[J]. Gastroenterology, 1998, 115(4):929-936. DOI:10.1016/s0016-5085(98)70265-3.] [DOI] [PubMed] [Google Scholar]
  • 6.FEDER J N, GNIRKE A, THOMAS W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13(4):399–408. doi: 10.1038/ng0896-399. [FEDER J N, GNIRKE A, THOMAS W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis[J]. Nat Genet, 1996, 13(4):399-408. DOI:10.1038/ng0896-399.] [DOI] [PubMed] [Google Scholar]
  • 7.ROETTO A, PAPANIKOLAOU G, POLITOU M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet. 2003;33(1):21–22. doi: 10.1038/ng1053. [ROETTO A, PAPANIKOLAOU G, POLITOU M, et al. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis[J]. Nat Genet, 2003, 33(1):21-22. DOI:10.1038/ng1053.] [DOI] [PubMed] [Google Scholar]
  • 8.PAPANIKOLAOU G, SAMUELS M E, LUDWIG E H, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet. 2004;36(1):77–82. doi: 10.1038/ng1274. [PAPANIKOLAOU G, SAMUELS M E, LUDWIG E H, et al. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis[J]. Nat Genet, 2004, 36(1):77-82. DOI:10.1038/ng1274.] [DOI] [PubMed] [Google Scholar]
  • 9.MONTOSI G, DONOVAN A, TOTARO A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108(4):619–623. doi: 10.1172/JCI13468. [MONTOSI G, DONOVAN A, TOTARO A, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene[J]. J Clin Invest, 2001, 108(4):619-623. DOI:10.1172/JCI13468.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.CAMASCHELLA C, ROETTO A, CALI A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25(1):14–15. doi: 10.1038/75534. [CAMASCHELLA C, ROETTO A, CALI A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22[J]. Nat Genet, 2000, 25(1):14-15. DOI:10.1038/75534.] [DOI] [PubMed] [Google Scholar]
  • 11.GUO S, JIANG S, EPPERLA N, et al. A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene. Blood. 2019;133(17):1888–1898. doi: 10.1182/blood-2018-10-879585. [GUO S, JIANG S, EPPERLA N, et al. A gene-based recessive diplotype exome scan discovers FGF6, a novel hepcidin-regulating iron-metabolism gene[J]. Blood, 2019, 133(17):1888-1898. DOI:10.1182/blood-2018-10-879585.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.DEV S, BABITT J L. Overview of iron metabolism in health and disease. Hemodial Int. 2017;21:S6–6S20. doi: 10.1111/hdi.12542. [DEV S, BABITT J L. Overview of iron metabolism in health and disease[J]. Hemodial Int, 2017, 21 Suppl 1:S6-6S20. DOI:10.1111/hdi.12542.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060–1072. doi: 10.1016/j.cell.2012.03.042. [DIXON S J, LEMBERG K M, LAMPRECHT M R, et al. Ferroptosis:an iron-dependent form of nonapoptotic cell death[J]. Cell, 2012, 149(5):1060-1072. DOI:10.1016/j.cell.2012.03.042.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.WANG H, AN P, XIE E, et al. Characterization of ferroptosis in murine models of hemochromatosis. Hepatology. 2017;66(2):449–465. doi: 10.1002/hep.29117. [WANG H, AN P, XIE E, et al. Characterization of ferroptosis in murine models of hemochromatosis[J]. Hepatology, 2017, 66(2):449-465. DOI:10.1002/hep.29117.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.FANG X, WANG H, HAN D, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A. 2019;116(7):2672–2680. doi: 10.1073/pnas.1821022116. [FANG X, WANG H, HAN D, et al. Ferroptosis as a target for protection against cardiomyopathy[J]. Proc Natl Acad Sci U S A, 2019, 116(7):2672-2680. DOI:10.1073/pnas.1821022116.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.PANTOPOULOS K. Iron metabolism and the IRE/IRP regulatory system:an update. Ann N Y Acad Sci. 2004;1012:1–13. doi: 10.1196/annals.1306.001. [PANTOPOULOS K. Iron metabolism and the IRE/IRP regulatory system:an update[J]. Ann N Y Acad Sci, 2004, 1012:1-13. DOI:10.1196/annals.1306.001.] [DOI] [PubMed] [Google Scholar]
  • 17.GANZ T, NEMETH E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders. Hematology Am Soc Hematol Educ Program. 2011;2011:538–542. doi: 10.1182/asheducation-2011.1.538. [GANZ T, NEMETH E. The hepcidin-ferroportin system as a therapeutic target in anemias and iron overload disorders[J]. Hematology Am Soc Hematol Educ Program, 2011, 2011:538-542. DOI:10.1182/asheducation-2011.1.538.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.NEMETH E, TUTTLE M S, POWELSON J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–2093. doi: 10.1126/science.1104742. [NEMETH E, TUTTLE M S, POWELSON J, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization[J]. Science, 2004, 306(5704):2090-2093. DOI:10.1126/science.1104742.] [DOI] [PubMed] [Google Scholar]
  • 19.BABITT J L, HUANG F W, WRIGHTING D M, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression. Nat Genet. 2006;38(5):531–539. doi: 10.1038/ng1777. [BABITT J L, HUANG F W, WRIGHTING D M, et al. Bone morphogenetic protein signaling by hemojuvelin regulates hepcidin expression[J]. Nat Genet, 2006, 38(5):531-539. DOI:10.1038/ng1777.] [DOI] [PubMed] [Google Scholar]
  • 20.CORRADINI E, MEYNARD D, WU Q, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6(BMP6)-SMAD signaling pathway in mice. Hepatology. 2011;54(1):273–284. doi: 10.1002/hep.24359. [CORRADINI E, MEYNARD D, WU Q, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6(BMP6)-SMAD signaling pathway in mice[J]. Hepatology, 2011, 54(1):273-284. DOI:10.1002/hep.24359.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.BABITT J L, HUANG F W, XIA Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance . J Clin Invest. 2007;117(7):1933–1939. doi: 10.1172/JCI31342. [BABITT J L, HUANG F W, XIA Y, et al. Modulation of bone morphogenetic protein signaling in vivo regulates systemic iron balance[J]. J Clin Invest, 2007, 117(7):1933-1939. DOI:10.1172/JCI31342. ] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.GOSWAMI T, ANDREWS N C. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem. 2006;281(39):28494–28498. doi: 10.1074/jbc.C600197200. [GOSWAMI T, ANDREWS N C. Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing[J]. J Biol Chem, 2006, 281(39):28494-28498. DOI:10.1074/jbc.C600197200.] [DOI] [PubMed] [Google Scholar]
  • 23.RAMOS E, KAUTZ L, RODRIGUEZ R, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice. Hepatology. 2011;53(4):1333–1341. doi: 10.1002/hep.24178. [RAMOS E, KAUTZ L, RODRIGUEZ R, et al. Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice[J]. Hepatology, 2011, 53(4):1333-1341. DOI:10.1002/hep.24178.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.SILVESTRI L, PAGANI A, NAI A, et al. The serine protease matriptase-2(TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell Metab. 2008;8(6):502–511. doi: 10.1016/j.cmet.2008.09.012. [SILVESTRI L, PAGANI A, NAI A, et al. The serine protease matriptase-2(TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin[J]. Cell Metab, 2008, 8(6):502-511. DOI:10.1016/j.cmet.2008.09.012.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.BIRD A. DNA methylation patterns and epigenetic memory. Genes Dev. 2002;16(1):6–21. doi: 10.1101/gad.947102. [BIRD A. DNA methylation patterns and epigenetic memory[J]. Genes Dev, 2002, 16(1):6-21. DOI:10.1101/gad.947102.] [DOI] [PubMed] [Google Scholar]
  • 26.YAMAMOTO M, TANAKA H, TOKI Y, et al. Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase. Int J Hematol. 2016;104(4):491–501. doi: 10.1007/s12185-016-2054-7. [YAMAMOTO M, TANAKA H, TOKI Y, et al. Iron-induced epigenetic abnormalities of mouse bone marrow through aberrant activation of aconitase and isocitrate dehydrogenase[J]. Int J Hematol, 2016, 104(4):491-501. DOI:10.1007/s12185-016-2054-7.] [DOI] [PubMed] [Google Scholar]
  • 27.YE Q, TRIVEDI M, ZHANG Y, et al. Brain iron loading impairs DNA methylation and alters GABAergic function in mice. FASEB J. 2019;33(2):2460–2471. doi: 10.1096/fj.201801116RR. [YE Q, TRIVEDI M, ZHANG Y, et al. Brain iron loading impairs DNA methylation and alters GABAergic function in mice[J]. FASEB J, 2019, 33(2):2460-2471. DOI:10.1096/fj.201801116RR.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.POGRIBNY I P, TRYNDYAK V P, POGRIBNA M, et al. Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents. Int J Oncol. 2013;42(5):1822–1832. doi: 10.3892/ijo.2013.1855. [POGRIBNY I P, TRYNDYAK V P, POGRIBNA M, et al. Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents[J]. Int J Oncol, 2013, 42(5):1822-1832. DOI:10.3892/ijo.2013.1855.] [DOI] [PubMed] [Google Scholar]
  • 29.DEVIREDDY L R, HART D O, GOETZ D H, et al. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell. 2010;141(6):1006–1017. doi: 10.1016/j.cell.2010.04.040. [DEVIREDDY L R, HART D O, GOETZ D H, et al. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production[J]. Cell, 2010, 141(6):1006-1017. DOI:10.1016/j.cell.2010.04.040.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.LIU Z, CIOCEA A, DEVIREDDY L. Endogenous siderophore 2, 5-dihydroxybenzoic acid deficiency promotes anemia and splenic iron overload in mice. Mol Cell Biol. 2014;34(13):2533–2546. doi: 10.1128/MCB.00231-14. [LIU Z, CIOCEA A, DEVIREDDY L. Endogenous siderophore 2, 5-dihydroxybenzoic acid deficiency promotes anemia and splenic iron overload in mice[J]. Mol Cell Biol, 2014, 34(13):2533-2546. DOI:10.1128/MCB.00231-14.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.ZHAO M, LI M Y, GAO X F, et al. Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4 + T cells of systemic lupus erythematosus . Clin Immunol. 2018;187:113–121. doi: 10.1016/j.clim.2017.11.002. [ZHAO M, LI M Y, GAO X F, et al. Downregulation of BDH2 modulates iron homeostasis and promotes DNA demethylation in CD4 + T cells of systemic lupus erythematosus[J]. Clin Immunol, 2018, 187:113-121. DOI:10.1016/j.clim.2017.11.002. ] [DOI] [PubMed] [Google Scholar]
  • 32.LU Q, KAPLAN M, RAY D, et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheum. 2002;46(5):1282–1291. doi: 10.1002/art.10234. [LU Q, KAPLAN M, RAY D, et al. Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus[J]. Arthritis Rheum, 2002, 46(5):1282-1291. DOI:10.1002/art.10234.] [DOI] [PubMed] [Google Scholar]
  • 33.KAPLAN M J, LU Q, WU A, et al. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4 + lupus T cells . J Immunol. 2004;172(6):3652–3661. doi: 10.4049/jimmunol.172.6.3652. [KAPLAN M J, LU Q, WU A, et al. Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4 + lupus T cells[J]. J Immunol, 2004, 172(6):3652-3661. DOI:10.4049/jimmunol.172.6.3652. ] [DOI] [PubMed] [Google Scholar]
  • 34.LU Q, WU A, RICHARDSON B C. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs. J Immunol. 2005;174(10):6212–6219. doi: 10.4049/jimmunol.174.10.6212. [LU Q, WU A, RICHARDSON B C. Demethylation of the same promoter sequence increases CD70 expression in lupus T cells and T cells treated with lupus-inducing drugs[J]. J Immunol, 2005, 174(10):6212-6219. DOI:10.4049/jimmunol.174.10.6212.] [DOI] [PubMed] [Google Scholar]
  • 35.LU Q, WU A, TESMER L, et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus. J Immunol. 2007;179(9):6352–6358. doi: 10.4049/jimmunol.179.9.6352. [LU Q, WU A, TESMER L, et al. Demethylation of CD40LG on the inactive X in T cells from women with lupus[J]. J Immunol, 2007, 179(9):6352-6358. DOI:10.4049/jimmunol.179.9.6352.] [DOI] [PubMed] [Google Scholar]
  • 36.WU H, ZHAO M, TAN L, et al. The key culprit in the pathogenesis of systemic lupus erythematosus:Aberrant DNA methylation. Autoimmun Rev. 2016;15(7):684–689. doi: 10.1016/j.autrev.2016.03.002. [WU H, ZHAO M, TAN L, et al. The key culprit in the pathogenesis of systemic lupus erythematosus:Aberrant DNA methylation[J]. Autoimmun Rev, 2016, 15(7):684-689. DOI:10.1016/j.autrev.2016.03.002.] [DOI] [PubMed] [Google Scholar]
  • 37.CORTELLINO S, XU J, SANNAI M, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell. 2011;146(1):67–79. doi: 10.1016/j.cell.2011.06.020. [CORTELLINO S, XU J, SANNAI M, et al. Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair[J]. Cell, 2011, 146(1):67-79. DOI:10.1016/j.cell.2011.06.020.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.ZHAO X, DAI J, MA Y, et al. Dynamics of ten-eleven translocation hydroxylase family proteins and 5-hydroxymethylcytosine in oligodendrocyte differentiation. Glia. 2014;62(6):914–926. doi: 10.1002/glia.22649. doi: 10.1002/glia.22649. [ZHAO X, DAI J, MA Y, et al. Dynamics of ten-eleven translocation hydroxylase family proteins and 5-hydroxymethylcytosine in oligodendrocyte differentiation[J]. Glia, 2014, 62(6):914-926. DOI:10.1002/glia.22649.] [DOI] [PubMed] [Google Scholar]
  • 39.ZHAO M H, LIANG S, GUO J, et al. Analysis of ferrous on ten-eleven translocation activity and epigenetic modifications of early mouse embryos by fluorescence microscopy. Microsc Microanal. 2016;22(2):342–348. doi: 10.1017/S1431927616000040. [ZHAO M H, LIANG S, GUO J, et al. Analysis of ferrous on ten-eleven translocation activity and epigenetic modifications of early mouse embryos by fluorescence microscopy[J]. Microsc Microanal, 2016, 22(2):342-348. DOI:10.1017/S1431927616000040.] [DOI] [PubMed] [Google Scholar]
  • 40.YAN H, WANG Y, QU X, et al. Distinct roles for TET family proteins in regulating human erythropoiesis. Blood. 2017;129(14):2002–2012. doi: 10.1182/blood-2016-08-736587. [YAN H, WANG Y, QU X, et al. Distinct roles for TET family proteins in regulating human erythropoiesis[J]. Blood, 2017, 129(14):2002-2012. DOI:10.1182/blood-2016-08-736587.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.INOKURA K, FUJIWARA T, SAITO K, et al. Impact of TET2 deficiency on iron metabolism in erythroblasts. Exp Hematol. 2017;49:56–67. doi: 10.1016/j.exphem.2017.01.002. [INOKURA K, FUJIWARA T, SAITO K, et al. Impact of TET2 deficiency on iron metabolism in erythroblasts[J]. Exp Hematol, 2017, 49:56-67.e5. DOI:10.1016/j.exphem.2017.01.002.] [DOI] [PubMed] [Google Scholar]
  • 42.GUO S, JIANG X, WANG Y, et al. The protective role of TET2 in erythroid iron homeostasis against oxidative stress and erythropoiesis. Cell Signal. 2017;38:106–115. doi: 10.1016/j.cellsig.2017.07.002. [GUO S, JIANG X, WANG Y, et al. The protective role of TET2 in erythroid iron homeostasis against oxidative stress and erythropoiesis[J]. Cell Signal, 2017, 38:106-115. DOI:10.1016/j.cellsig.2017.07.002.] [DOI] [PubMed] [Google Scholar]
  • 43.PINNIX Z K, MILLER L D, WANG W, et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med. 2010;2(43):43ra56. doi: 10.1126/scisignal.3001127. [PINNIX Z K, MILLER L D, WANG W, et al. Ferroportin and iron regulation in breast cancer progression and prognosis[J]. Sci Transl Med, 2010, 2(43):43ra56. DOI:10.1126/scisignal.3001127.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.CHEN Y, ZHANG S, WANG X, et al. Disordered signaling governing ferroportin transcription favors breast cancer growth. Cell Signal. 2015;27(1):168–176. doi: 10.1016/j.cellsig.2014.11.002. [CHEN Y, ZHANG S, WANG X, et al. Disordered signaling governing ferroportin transcription favors breast cancer growth[J]. Cell Signal, 2015, 27(1):168-176. DOI:10.1016/j.cellsig.2014.11.002.] [DOI] [PubMed] [Google Scholar]
  • 45.ZHANG S, CHANG W, WU H, et al. Pan-cancer analysis of iron metabolic landscape across the Cancer Genome Atlas. J Cell Physiol. 2020;235(2):1013–1024. doi: 10.1002/jcp.29017. [ZHANG S, CHANG W, WU H, et al. Pan-cancer analysis of iron metabolic landscape across the Cancer Genome Atlas[J]. J Cell Physiol, 2020, 235(2):1013-1024. DOI:10.1002/jcp.29017.] [DOI] [PubMed] [Google Scholar]
  • 46.UDALI S, CASTAGNA A, CORBELLA M, et al. Hepcidin and DNA promoter methylation in hepatocellular carcinoma. Eur J Clin Invest. 2018;48(2):e12870. doi: 10.1111/eci.12870. [UDALI S, CASTAGNA A, CORBELLA M, et al. Hepcidin and DNA promoter methylation in hepatocellular carcinoma[J/OL]. Eur J Clin Invest, 2018, 48(2):e12870. DOI:10.1111/eci.12870.] [DOI] [PubMed] [Google Scholar]
  • 47.SHARP P A, CLARKSON R, HUSSAIN A, et al. DNA methylation of hepatic iron sensing genes and the regulation of hepcidin expression. PLoS One. 2018;13(5):e0197863. doi: 10.1371/journal.pone.0197863. [SHARP P A, CLARKSON R, HUSSAIN A, et al. DNA methylation of hepatic iron sensing genes and the regulation of hepcidin expression[J/OL]. PLoS One, 2018, 13(5):e0197863. DOI:10.1371/journal.pone.0197863.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.HUANG Y, ZHANG H, WANG C, et al. DNA methylation suppresses liver Hamp expression in response to iron deficiency after bariatric surgery. Surg Obes Relat Dis. 2020;16(1):109–118. doi: 10.1016/j.soard.2019.10.005. [HUANG Y, ZHANG H, WANG C, et al. DNA methylation suppresses liver Hamp expression in response to iron deficiency after bariatric surgery[J]. Surg Obes Relat Dis, 2020, 16(1):109-118. DOI:10.1016/j.soard.2019.10.005.] [DOI] [PubMed] [Google Scholar]
  • 49.SHUCHENG G, CHUNKANG C, YOUSHAN Z, et al. Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients. Cancer Invest. 2015;33(4):98–106. doi: 10.3109/07357907.2014.1001895. [SHUCHENG G, CHUNKANG C, YOUSHAN Z, et al. Decitabine treatment could ameliorate primary iron-overload in myelodysplastic syndrome patients[J]. Cancer Invest, 2015, 33(4):98-106. DOI:10.3109/07357907.2014.1001895.] [DOI] [PubMed] [Google Scholar]
  • 50.HE Y, CUI Y, XU B, et al. Hypermethylation leads to bone morphogenetic protein 6 downregulation in hepatocellular carcinoma. PLoS One. 2014;9(1):e87994. doi: 10.1371/journal.pone.0087994. [HE Y, CUI Y, XU B, et al. Hypermethylation leads to bone morphogenetic protein 6 downregulation in hepatocellular carcinoma[J/OL]. PLoS One, 2014, 9(1):e87994. DOI:10.1371/journal.pone.0087994.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.KORNBERG R D. Structure of chromatin. Annu Rev Biochem. 1977;46:931–954. doi: 10.1146/annurev.bi.46.070177.004435. [KORNBERG R D. Structure of chromatin[J]. Annu Rev Biochem, 1977, 46:931-954. DOI:10.1146/annurev.bi.46.070177.004435.] [DOI] [PubMed] [Google Scholar]
  • 52.KORNBERG R D. Chromatin structure:a repeating unit of histones and DNA. Science. 1974;184(4139):868–871. doi: 10.1126/science.184.4139.868. [KORNBERG R D. Chromatin structure:a repeating unit of histones and DNA[J]. Science, 1974, 184(4139):868-871. DOI:10.1126/science.184.4139.868.] [DOI] [PubMed] [Google Scholar]
  • 53.KOUZARIDES T. Chromatin modifications and their function. Cell. 2007;128(4):693–705. doi: 10.1016/j.cell.2007.02.005. [KOUZARIDES T. Chromatin modifications and their function[J]. Cell, 2007, 128(4):693-705. DOI:10.1016/j.cell.2007.02.005.] [DOI] [PubMed] [Google Scholar]
  • 54.SMITH B C, DENU J M. Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta. 2009;1789(1):45–57. doi: 10.1016/j.bbagrm.2008.06.005. [SMITH B C, DENU J M. Chemical mechanisms of histone lysine and arginine modifications[J]. Biochim Biophys Acta, 2009, 1789(1):45-57. DOI:10.1016/j.bbagrm.2008.06.005.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.BERNSTEIN B E, MEISSNER A, LANDER E S. The mammalian epigenome. Cell. 2007;128(4):669–681. doi: 10.1016/j.cell.2007.01.033. [BERNSTEIN B E, MEISSNER A, LANDER E S. The mammalian epigenome[J]. Cell, 2007, 128(4):669-681. DOI:10.1016/j.cell.2007.01.033.] [DOI] [PubMed] [Google Scholar]
  • 56.SILVA P F, GARCIA V A, DORNELLES ADA S, et al. Memory impairment induced by brain iron overload is accompanied by reduced H3K9 acetylation and ameliorated by sodium butyrate. Neuroscience. 2012;200:42–49. doi: 10.1016/j.neuroscience.2011.10.038. [SILVA P F, GARCIA V A, DORNELLES ADA S, et al. Memory impairment induced by brain iron overload is accompanied by reduced H3K9 acetylation and ameliorated by sodium butyrate[J]. Neuroscience, 2012, 200:42-49. DOI:10.1016/j.neuroscience.2011.10.038.] [DOI] [PubMed] [Google Scholar]
  • 57.GNANA-PRAKASAM J P, VEERANAN-KARMEGAM R, COOTHANKANDASWAMY V, et al. Loss of Hfe leads to progression of tumor phenotype in primary retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 2013;54(1):63–71. doi: 10.1167/iovs.12-10312. [GNANA-PRAKASAM J P, VEERANAN-KARMEGAM R, COOTHANKANDASWAMY V, et al. Loss of Hfe leads to progression of tumor phenotype in primary retinal pigment epithelial cells[J]. Invest Ophthalmol Vis Sci, 2013, 54(1):63-71. DOI:10.1167/iovs.12-10312.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.INGRASSIA R, LANZILLOTTA A, SARNICO I, et al. 1B/(-)IRE DMT1 expression during brain ischemia contributes to cell death mediated by NF-kappaB/RelA acetylation at Lys310. PLoS One. 2012;7(5):e38019. doi: 10.1371/journal.pone.0038019. [INGRASSIA R, LANZILLOTTA A, SARNICO I, et al. 1B/(-)IRE DMT1 expression during brain ischemia contributes to cell death mediated by NF-kappaB/RelA acetylation at Lys310[J/OL]. PLoS One, 2012, 7(5):e38019. DOI:10.1371/journal.pone.0038019.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.WANG W, DI X, TORTI S V, et al. Ferritin H induction by histone deacetylase inhibitors. Biochem Pharmacol. 2010;80(3):316–324. doi: 10.1016/j.bcp.2010.04.008. [WANG W, DI X, TORTI S V, et al. Ferritin H induction by histone deacetylase inhibitors[J]. Biochem Pharmacol, 2010, 80(3):316-324. DOI:10.1016/j.bcp.2010.04.008.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.TAO Y, WU Q, GUO X, et al. MBD5 regulates iron metabolism via methylation-independent genomic targeting of Fth1 through KAT2A in mice. Br J Haematol. 2014;166(2):279–291. doi: 10.1111/bjh.12863. [TAO Y, WU Q, GUO X, et al. MBD5 regulates iron metabolism via methylation-independent genomic targeting of Fth1 through KAT2A in mice[J]. Br J Haematol, 2014, 166(2):279-291. DOI:10.1111/bjh.12863.] [DOI] [PubMed] [Google Scholar]
  • 61.YANG X, PARK S H, CHANG H C, et al. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2. J Clin Invest. 2017;127(4):1505–1516. doi: 10.1172/JCI88574. [YANG X, PARK S H, CHANG H C, et al. Sirtuin 2 regulates cellular iron homeostasis via deacetylation of transcription factor NRF2[J]. J Clin Invest, 2017, 127(4):1505-1516. DOI:10.1172/JCI88574.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.WANG R H, LI C, XU X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression. Cell Metab. 2005;2(6):399–409. doi: 10.1016/j.cmet.2005.10.010. [WANG R H, LI C, XU X, et al. A role of SMAD4 in iron metabolism through the positive regulation of hepcidin expression[J]. Cell Metab, 2005, 2(6):399-409. DOI:10.1016/j.cmet.2005.10.010.] [DOI] [PubMed] [Google Scholar]
  • 63.LIU H, TRINH T L, DONG H, et al. Iron regulator hepcidin exhibits antiviral activity against hepatitis C virus. PLoS One. 2012;7(10):e46631. doi: 10.1371/journal.pone.0046631. [LIU H, TRINH T L, DONG H, et al. Iron regulator hepcidin exhibits antiviral activity against hepatitis C virus[J/OL]. PLoS One, 2012, 7(10):e46631. DOI:10.1371/journal.pone.0046631.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.MIURA K, TAURA K, KODAMA Y, et al. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity. Hepatology. 2008;48(5):1420–1429. doi: 10.1002/hep.22486. [MIURA K, TAURA K, KODAMA Y, et al. Hepatitis C virus-induced oxidative stress suppresses hepcidin expression through increased histone deacetylase activity[J]. Hepatology, 2008, 48(5):1420-1429. DOI:10.1002/hep.22486.] [DOI] [PubMed] [Google Scholar]
  • 65.PASRICHA S R, LIM P J, DUARTE T L, et al. Hepcidin is regulated by promoter-associated histone acetylation and HDAC3. Nat Commun. 2017;8(1):403. doi: 10.1038/s41467-017-00500-z. [PASRICHA S R, LIM P J, DUARTE T L, et al. Hepcidin is regulated by promoter-associated histone acetylation and HDAC3[J]. Nat Commun, 2017, 8(1):403. DOI:10.1038/s41467-017-00500-z.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.KANAMORI Y, MURAKAMI M, MATSUI T, et al. Hepcidin expression in liver cells:evaluation of mRNA levels and transcriptional regulation. Gene. 2014;546(1):50–55. doi: 10.1016/j.gene.2014.05.040. [KANAMORI Y, MURAKAMI M, MATSUI T, et al. Hepcidin expression in liver cells:evaluation of mRNA levels and transcriptional regulation[J]. Gene, 2014, 546(1):50-55. DOI:10.1016/j.gene.2014.05.040.] [DOI] [PubMed] [Google Scholar]
  • 67.GAUN V, PATCHEN B, VOLOVETZ J, et al. A chemical screen identifies small molecules that regulate hepcidin expression. Blood Cells Mol Dis. 2014;53(4):231–240. doi: 10.1016/j.bcmd.2014.06.002. [GAUN V, PATCHEN B, VOLOVETZ J, et al. A chemical screen identifies small molecules that regulate hepcidin expression[J]. Blood Cells Mol Dis, 2014, 53(4):231-240. DOI:10.1016/j.bcmd.2014.06.002.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.YIN X, WU Q, MONGA J, et al. HDAC1 governs iron homeostasis independent of histone deacetylation in iron-overload murine models. Antioxid Redox Signal. 2018;28(13):1224–1237. doi: 10.1089/ars.2017.7161. [YIN X, WU Q, MONGA J, et al. HDAC1 governs iron homeostasis independent of histone deacetylation in iron-overload murine models[J]. Antioxid Redox Signal, 2018, 28(13):1224-1237. DOI:10.1089/ars.2017.7161.] [DOI] [PubMed] [Google Scholar]
  • 69.SHI Y, LAN F, MATSON C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell. 2004;119(7):941–953. doi: 10.1016/j.cell.2004.12.012. [SHI Y, LAN F, MATSON C, et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1[J]. Cell, 2004, 119(7):941-953. DOI:10.1016/j.cell.2004.12.012.] [DOI] [PubMed] [Google Scholar]
  • 70.MOSAMMAPARAST N, SHI Y. Reversal of histone methylation:biochemical and molecular mechanisms of histone demethylases. Annu Rev Biochem. 2010;79:155–179. doi: 10.1146/annurev.biochem.78.070907.103946. [MOSAMMAPARAST N, SHI Y. Reversal of histone methylation:biochemical and molecular mechanisms of histone demethylases[J]. Annu Rev Biochem, 2010, 79:155-179. DOI:10.1146/annurev.biochem.78.070907.103946.] [DOI] [PubMed] [Google Scholar]
  • 71.HAYWARD D, COLE P A. LSD1 histone demethylase assays and inhibition. Methods Enzymol. 2016;573:261–278. doi: 10.1016/bs.mie.2016.01.020. [HAYWARD D, COLE P A. LSD1 histone demethylase assays and inhibition[J]. Methods Enzymol, 2016, 573:261-278. DOI:10.1016/bs.mie.2016.01.020.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.MAIQUES-DIAZ A, SOMERVAILLE T C. LSD1:biologic roles and therapeutic targeting. Epigenomics. 2016;8(8):1103–1116. doi: 10.2217/epi-2016-0009. [MAIQUES-DIAZ A, SOMERVAILLE T C. LSD1:biologic roles and therapeutic targeting[J]. Epigenomics, 2016, 8(8):1103-1116. DOI:10.2217/epi-2016-0009.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.SORNA V, THEISEN E R, STEPHENS B, et al. High-throughput virtual screening identifies novel N'-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors. J Med Chem. 2013;56(23):9496–9508. doi: 10.1021/jm400870h. [SORNA V, THEISEN E R, STEPHENS B, et al. High-throughput virtual screening identifies novel N'-(1-phenylethylidene)-benzohydrazides as potent, specific, and reversible LSD1 inhibitors[J]. J Med Chem, 2013, 56(23):9496-9508. DOI:10.1021/jm400870h.] [DOI] [PubMed] [Google Scholar]
  • 74.SARNO F, PAPULINO C, FRANCI G, et al. 3-chloro-n'-(2-hydroxybenzylidene) benzohydrazide:an LSD1-selective inhibitor and iron-chelating agent for anticancer therapy. Front Pharmacol. 2018;9:1006. doi: 10.3389/fphar.2018.01006. [SARNO F, PAPULINO C, FRANCI G, et al. 3-chloro-n'-(2-hydroxybenzylidene) benzohydrazide:an LSD1-selective inhibitor and iron-chelating agent for anticancer therapy[J]. Front Pharmacol, 2018, 9:1006. DOI:10.3389/fphar.2018.01006.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.ROATSCH M, HOFFMANN I, ABBOUD M I, et al. The clinically used iron chelator deferasirox is an inhibitor of epigenetic JumonjiC domain-containing histone demethylases. ACS Chem Biol. 2019;14(8):1737–1750. doi: 10.1021/acschembio.9b00289. [ROATSCH M, HOFFMANN I, ABBOUD M I, et al. The clinically used iron chelator deferasirox is an inhibitor of epigenetic JumonjiC domain-containing histone demethylases[J]. ACS Chem Biol, 2019, 14(8):1737-1750. DOI:10.1021/acschembio.9b00289.] [DOI] [PubMed] [Google Scholar]
  • 76.CAO L L, LIU H, YUE Z, et al. Iron chelation inhibits cancer cell growth and modulates global histone methylation status in colorectal cancer. Biometals. 2018;31(5):797–805. doi: 10.1007/s10534-018-0123-5. [CAO L L, LIU H, YUE Z, et al. Iron chelation inhibits cancer cell growth and modulates global histone methylation status in colorectal cancer[J]. Biometals, 2018, 31(5):797-805. DOI:10.1007/s10534-018-0123-5.] [DOI] [PubMed] [Google Scholar]
  • 77.JIANG Y, LI C, WU Q, et al. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses. Nat Commun. 2019;10(1):2935. doi: 10.1038/s41467-019-11002-5. [JIANG Y, LI C, WU Q, et al. Iron-dependent histone 3 lysine 9 demethylation controls B cell proliferation and humoral immune responses[J]. Nat Commun, 2019, 10(1):2935. DOI:10.1038/s41467-019-11002-5.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.HEO I, KIM V N. Regulating the regulators:posttranslational modifications of RNA silencing factors. Cell. 2009;139(1):28–31. doi: 10.1016/j.cell.2009.09.013. [HEO I, KIM V N. Regulating the regulators:posttranslational modifications of RNA silencing factors[J]. Cell, 2009, 139(1):28-31. DOI:10.1016/j.cell.2009.09.013.] [DOI] [PubMed] [Google Scholar]
  • 79.BARTEL D P. MicroRNAs:genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–297. doi: 10.1016/s0092-8674(04)00045-5. [BARTEL D P. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell, 2004, 116(2):281-297. DOI:10.1016/s0092-8674(04)00045-5.] [DOI] [PubMed] [Google Scholar]
  • 80.CARTHEW R W, SONTHEIMER E J. Origins and mechanisms of miRNAs and siRNAs. Cell. 2009;136(4):642–655. doi: 10.1016/j.cell.2009.01.035. [CARTHEW R W, SONTHEIMER E J. Origins and mechanisms of miRNAs and siRNAs[J]. Cell, 2009, 136(4):642-655. DOI:10.1016/j.cell.2009.01.035.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.ANDOLFO I, DE FALCO L, ASCI R, et al. Regulation of divalent metal transporter 1(DMT1) non-IRE isoform by the microRNA Let-7d in erythroid cells. Haematologica. 2010;95(8):1244–1252. doi: 10.3324/haematol.2009.020685. [ANDOLFO I, DE FALCO L, ASCI R, et al. Regulation of divalent metal transporter 1(DMT1) non-IRE isoform by the microRNA Let-7d in erythroid cells[J]. Haematologica, 2010, 95(8):1244-1252. DOI:10.3324/haematol.2009.020685.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.JIANG S, GUO S, LI H, et al. Identification and functional verification of microRNA-16 family targeting intestinal divalent metal transporter 1(DMT1) in vitro and in vivo . Front Physiol. 2019;10:819. doi: 10.3389/fphys.2019.00819. [JIANG S, GUO S, LI H, et al. Identification and functional verification of microRNA-16 family targeting intestinal divalent metal transporter 1(DMT1) in vitro and in vivo[J]. Front Physiol, 2019, 10:819. DOI:10.3389/fphys.2019.00819. ] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.BABU K R, MUCKENTHALER M U. miR-20a regulates expression of the iron exporter ferroportin in lung cancer. J Mol Med (Berl) 2016;94(3):347–359. doi: 10.1007/s00109-015-1362-3. [BABU K R, MUCKENTHALER M U. miR-20a regulates expression of the iron exporter ferroportin in lung cancer[J]. J Mol Med (Berl), 2016, 94(3):347-359.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.JIANG S, FANG X, LIU M, et al. MiR-20b down-regulates intestinal ferroportin expression in vitro and in vivo . Cells. 2019;8(10) doi: 10.3390/cells8101135. [JIANG S, FANG X, LIU M, et al. MiR-20b down-regulates intestinal ferroportin expression in vitro and in vivo[J]. Cells, 2019, 8(10). DOI:10.3390/cells8101135. ] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.SANGOKOYA C, DOSS J F, CHI J T. Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin. PLoS Genet. 2013;9(4):e1003408. doi: 10.1371/journal.pgen.1003408. [SANGOKOYA C, DOSS J F, CHI J T. Iron-responsive miR-485-3p regulates cellular iron homeostasis by targeting ferroportin[J/OL]. PLoS Genet, 2013, 9(4):e1003408. DOI:10.1371/journal.pgen.1003408.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.YOSHIOKA Y, KOSAKA N, OCHIYA T, et al. Micromanaging iron homeostasis:hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins. J Biol Chem. 2012;287(41):34110–34119. doi: 10.1074/jbc.M112.356717. [YOSHIOKA Y, KOSAKA N, OCHIYA T, et al. Micromanaging iron homeostasis:hypoxia-inducible micro-RNA-210 suppresses iron homeostasis-related proteins[J]. J Biol Chem, 2012, 287(41):34110-34119. DOI:10.1074/jbc.M112.356717.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87.SCHAAR D G, MEDINA D J, MOORE D F, et al. miR-320 targets transferrin receptor 1(CD71) and inhibits cell proliferation. Exp Hematol. 2009;37(2):245–255. doi: 10.1016/j.exphem.2008.10.002. [SCHAAR D G, MEDINA D J, MOORE D F, et al. miR-320 targets transferrin receptor 1(CD71) and inhibits cell proliferation[J]. Exp Hematol, 2009, 37(2):245-255. DOI:10.1016/j.exphem.2008.10.002.] [DOI] [PubMed] [Google Scholar]
  • 88.KINDRAT I, TRYNDYAK V, DE CONTI A, et al. MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis. Oncotarget. 2016;7(2):1276–1287. doi: 10.18632/oncotarget.6004. [KINDRAT I, TRYNDYAK V, DE CONTI A, et al. MicroRNA-152-mediated dysregulation of hepatic transferrin receptor 1 in liver carcinogenesis[J]. Oncotarget, 2016, 7(2):1276-1287. DOI:10.18632/oncotarget.6004.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.BABU K R, MUCKENTHALER M U. miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma. Sci Rep. 2019;9(1):1518. doi: 10.1038/s41598-018-35947-7. [BABU K R, MUCKENTHALER M U. miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma[J]. Sci Rep, 2019, 9(1):1518. DOI:10.1038/s41598-018-35947-7.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90.MIYAZAWA M, BOGDAN A R, HASHIMOTO K, et al. Regulation of transferrin receptor-1 mRNA by the interplay between IRE-binding proteins and miR-7/miR-141 in the 3'-IRE stem-loops. RNA. 2018;24(4):468–479. doi: 10.1261/rna.063941.117. [MIYAZAWA M, BOGDAN A R, HASHIMOTO K, et al. Regulation of transferrin receptor-1 mRNA by the interplay between IRE-binding proteins and miR-7/miR-141 in the 3'-IRE stem-loops[J]. RNA, 2018, 24(4):468-479. DOI:10.1261/rna.063941.117.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.CHAN S Y, ZHANG Y Y, HEMANN C, et al. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metab. 2009;10(4):273–284. doi: 10.1016/j.cmet.2009.08.015. [CHAN S Y, ZHANG Y Y, HEMANN C, et al. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2[J]. Cell Metab, 2009, 10(4):273-284. DOI:10.1016/j.cmet.2009.08.015.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 92.ASCI R, VALLEFUOCO F, ANDOLFO I, et al. Trasferrin receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP(+) as Parkinson's disease cellular model. Neurosci Res. 2013;77(3):121–127. doi: 10.1016/j.neures.2013.09.003. [ASCI R, VALLEFUOCO F, ANDOLFO I, et al. Trasferrin receptor 2 gene regulation by microRNA 221 in SH-SY5Y cells treated with MPP(+) as Parkinson's disease cellular model[J]. Neurosci Res, 2013, 77(3):121-127. DOI:10.1016/j.neures.2013.09.003.] [DOI] [PubMed] [Google Scholar]
  • 93.SRINOUN K, SATHIRAPONGSASUTI N, PAIBOONSUKWONG K, et al. miR-144 regulates oxidative stress tolerance of thalassemic erythroid cell via targeting NRF2. Ann Hematol. 2019;98(9):2045–2052. doi: 10.1007/s00277-019-03737-4. [SRINOUN K, SATHIRAPONGSASUTI N, PAIBOONSUKWONG K, et al. miR-144 regulates oxidative stress tolerance of thalassemic erythroid cell via targeting NRF2[J]. Ann Hematol, 2019, 98(9):2045-2052. DOI:10.1007/s00277-019-03737-4.] [DOI] [PubMed] [Google Scholar]
  • 94.SHPYLEVA S I, TRYNDYAK V P, KOVALCHUK O, et al. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat. 2011;126(1):63–71. doi: 10.1007/s10549-010-0849-4. [SHPYLEVA S I, TRYNDYAK V P, KOVALCHUK O, et al. Role of ferritin alterations in human breast cancer cells[J]. Breast Cancer Res Treat, 2011, 126(1):63-71. DOI:10.1007/s10549-010-0849-4.] [DOI] [PubMed] [Google Scholar]
  • 95.RIPA R, DOLFI L, TERRIGNO M, et al. MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging. BMC Biol. 2017;15(1):9. doi: 10.1186/s12915-017-0354-x. [RIPA R, DOLFI L, TERRIGNO M, et al. MicroRNA miR-29 controls a compensatory response to limit neuronal iron accumulation during adult life and aging[J]. BMC Biol, 2017, 15(1):9. DOI:10.1186/s12915-017-0354-x.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96.ZUMBRENNEN-BULLOUGH K B, WU Q, CORE A B, et al. MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription. J Biol Chem. 2014;289(34):23796–23808. doi: 10.1074/jbc.M114.577387. [ZUMBRENNEN-BULLOUGH K B, WU Q, CORE A B, et al. MicroRNA-130a is up-regulated in mouse liver by iron deficiency and targets the bone morphogenetic protein (BMP) receptor ALK2 to attenuate BMP signaling and hepcidin transcription[J]. J Biol Chem, 2014, 289(34):23796-23808. DOI:10.1074/jbc.M114.577387.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.CASTOLDI M, VUJIC SPASIC M, ALTAMURA S, et al. The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice. J Clin Invest. 2011;121(4):1386–1396. doi: 10.1172/JCI44883. [CASTOLDI M, VUJIC SPASIC M, ALTAMURA S, et al. The liver-specific microRNA miR-122 controls systemic iron homeostasis in mice[J]. J Clin Invest, 2011, 121(4):1386-1396. DOI:10.1172/JCI44883.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.LI Y, LIU S, SUN H, et al. MiR-218 inhibits erythroid differentiation and alters iron metabolism by targeting ALAS2 in K562 cells. Int J Mol Sci. 2015;16(12):28156–28168. doi: 10.3390/ijms161226088. [LI Y, LIU S, SUN H, et al. MiR-218 inhibits erythroid differentiation and alters iron metabolism by targeting ALAS2 in K562 cells[J]. Int J Mol Sci, 2015, 16(12):28156-28168. DOI:10.3390/ijms161226088.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.AZZOUZI I, MOEST H, WINKLER J, et al. MicroRNA-96 directly inhibits gamma-globin expression in human erythropoiesis. PLoS One. 2011;6(7):e22838. doi: 10.1371/journal.pone.0022838. [AZZOUZI I, MOEST H, WINKLER J, et al. MicroRNA-96 directly inhibits gamma-globin expression in human erythropoiesis[J/OL]. PLoS One, 2011, 6(7):e22838. DOI:10.1371/journal.pone.0022838.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.HOU W, TIAN Q, STEUERWALD N M, et al. The let-7 microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates oxidant injury in human hepatocytes. Biochim Biophys Acta. 2012;1819(11-12):1113–1122. doi: 10.1016/j.bbagrm.2012.06.001. [HOU W, TIAN Q, STEUERWALD N M, et al. The let-7 microRNA enhances heme oxygenase-1 by suppressing Bach1 and attenuates oxidant injury in human hepatocytes[J]. Biochim Biophys Acta, 2012, 1819(11-12):1113-1122. DOI:10.1016/j.bbagrm.2012.06.001.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.HOU W, TIAN Q, ZHENG J, et al. MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins. Hepatology. 2010;51(5):1494–1504. doi: 10.1002/hep.23401. [HOU W, TIAN Q, ZHENG J, et al. MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins[J]. Hepatology, 2010, 51(5):1494-1504. DOI:10.1002/hep.23401.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.XING Y, LI J, LI S P, et al. MiR-27a-5p regulates apoptosis of liver ischemia-reperfusion injury in mice by targeting Bach1. J Cell Biochem. 2018;119(12):10376–10383. doi: 10.1002/jcb.27383. [XING Y, LI J, LI S P, et al. MiR-27a-5p regulates apoptosis of liver ischemia-reperfusion injury in mice by targeting Bach1[J]. J Cell Biochem, 2018, 119(12):10376-10383. DOI:10.1002/jcb.27383.] [DOI] [PubMed] [Google Scholar]
  • 103.LIAO Y, DU X, LÖNNERDAL B. miR-214 regulates lactoferrin expression and pro-apoptotic function in mammary epithelial cells. J Nutr. 2010;140(9):1552–1556. doi: 10.3945/jn.110.124289. [LIAO Y, DU X, LÖNNERDAL B. miR-214 regulates lactoferrin expression and pro-apoptotic function in mammary epithelial cells[J]. J Nutr, 2010, 140(9):1552-1556. DOI:10.3945/jn.110.124289.] [DOI] [PubMed] [Google Scholar]
  • 104.LIAO Y, LÖNNERDAL B. miR-584 mediates post-transcriptional expression of lactoferrin receptor in Caco-2 cells and in mouse small intestine during the perinatal period. Int J Biochem Cell Biol. 2010;42(8):1363–1369. doi: 10.1016/j.biocel.2009.07.019. [LIAO Y, LÖNNERDAL B. miR-584 mediates post-transcriptional expression of lactoferrin receptor in Caco-2 cells and in mouse small intestine during the perinatal period[J]. Int J Biochem Cell Biol, 2010, 42(8):1363-1369. DOI:10.1016/j.biocel.2009.07.019.] [DOI] [PubMed] [Google Scholar]
  • 105.GATTER K C, BROWN G, TROWBRIDGE I S, et al. Transferrin receptors in human tissues:their distribution and possible clinical relevance. J Clin Pathol. 1983;36(5):539–545. doi: 10.1136/jcp.36.5.539. [GATTER K C, BROWN G, TROWBRIDGE I S, et al. Transferrin receptors in human tissues:their distribution and possible clinical relevance[J]. J Clin Pathol, 1983, 36(5):539-545. DOI:10.1136/jcp.36.5.539.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.WU K J, POLACK A, DALLA-FAVERA R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science. 1999;283(5402):676–679. doi: 10.1126/science.283.5402.676. [WU K J, POLACK A, DALLA-FAVERA R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC[J]. Science, 1999, 283(5402):676-679. DOI:10.1126/science.283.5402.676.] [DOI] [PubMed] [Google Scholar]
  • 107.ZHANG F, WANG W, TSUJI Y, et al. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem. 2008;283(49):33911–33918. doi: 10.1074/jbc.M806432200. [ZHANG F, WANG W, TSUJI Y, et al. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest[J]. J Biol Chem, 2008, 283(49):33911-33918. DOI:10.1074/jbc.M806432200.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108.BAUMGART M, GROTH M, PRIEBE S, et al. Age-dependent regulation of tumor-related microRNAs in the brain of the annual fish Nothobranchius furzeri. Mech Ageing Dev. 2012;133(5):226–233. doi: 10.1016/j.mad.2012.03.015. [BAUMGART M, GROTH M, PRIEBE S, et al. Age-dependent regulation of tumor-related microRNAs in the brain of the annual fish Nothobranchius furzeri[J]. Mech Ageing Dev, 2012, 133(5):226-233. DOI:10.1016/j.mad.2012.03.015.] [DOI] [PubMed] [Google Scholar]
  • 109.UGALDE A P, RAMSAY A J, DE LA ROSA J, et al. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53. EMBO J. 2011;30(11):2219–2232. doi: 10.1038/emboj.2011.124. [UGALDE A P, RAMSAY A J, DE LA ROSA J, et al. Aging and chronic DNA damage response activate a regulatory pathway involving miR-29 and p53[J]. EMBO J, 2011, 30(11):2219-2232. DOI:10.1038/emboj.2011.124.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.SOMEL M, GUO S, FU N, et al. MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Res. 2010;20(9):1207–1218. doi: 10.1101/gr.106849.110. [SOMEL M, GUO S, FU N, et al. MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain[J]. Genome Res, 2010, 20(9):1207-1218. DOI:10.1101/gr.106849.110.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111.LAGOS-QUINTANA M, RAUHUT R, YALCIN A, et al. Identification of tissue-specific microRNAs from mouse. Curr Biol. 2002;12(9):735–739. doi: 10.1016/s0960-9822(02)00809-6. [LAGOS-QUINTANA M, RAUHUT R, YALCIN A, et al. Identification of tissue-specific microRNAs from mouse[J]. Curr Biol, 2002, 12(9):735-739. DOI:10.1016/s0960-9822(02)00809-6.] [DOI] [PubMed] [Google Scholar]
  • 112.LANDGRAF P, RUSU M, SHERIDAN R, et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell. 2007;129(7):1401–1414. doi: 10.1016/j.cell.2007.04.040. [LANDGRAF P, RUSU M, SHERIDAN R, et al. A mammalian microRNA expression atlas based on small RNA library sequencing[J]. Cell, 2007, 129(7):1401-1414. DOI:10.1016/j.cell.2007.04.040.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.HENTZE M W, MUCKENTHALER M U, GALY B, et al. Two to tango:regulation of Mammalian iron metabolism. Cell. 2010;142(1):24–38. doi: 10.1016/j.cell.2010.06.028. [HENTZE M W, MUCKENTHALER M U, GALY B, et al. Two to tango:regulation of Mammalian iron metabolism[J]. Cell, 2010, 142(1):24-38. DOI:10.1016/j.cell.2010.06.028.] [DOI] [PubMed] [Google Scholar]
  • 114.LISTOWSKI M A, HEGER E, BOGUSŁAWSKA D M, et al. microRNAs:fine tuning of erythropoiesis. Cell Mol Biol Lett. 2013;18(1):34–46. doi: 10.2478/s11658-012-0038-z. [LISTOWSKI M A, HEGER E, BOGUSŁAWSKA D M, et al. microRNAs:fine tuning of erythropoiesis[J]. Cell Mol Biol Lett, 2013, 18(1):34-46. DOI:10.2478/s11658-012-0038-z.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.JONES P A, BAYLIN S B. The epigenomics of cancer. Cell. 2007;128(4):683–692. doi: 10.1016/j.cell.2007.01.029. [JONES P A, BAYLIN S B. The epigenomics of cancer[J]. Cell, 2007, 128(4):683-692. DOI:10.1016/j.cell.2007.01.029.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116.TABERLAY P C, JONES P A. DNA methylation and cancer. Prog Drug Res. 2011;67:1–23. doi: 10.1007/978-3-7643-8989-5_1. [TABERLAY P C, JONES P A. DNA methylation and cancer[J]. Prog Drug Res, 2011, 67:1-23. DOI:10.1007/978-3-7643-8989-5_1.] [DOI] [PubMed] [Google Scholar]

Articles from Journal of Zhejiang University (Medical Sciences) are provided here courtesy of Zhejiang University Press

RESOURCES