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. 2017 Jun 1;18:428. doi: 10.1186/s12864-017-3811-6

The Binding Sites of miR-619-5p in the mRNAs of Human and Orthologous Genes

Shara Atambayeva 1,✉, Raigul Niyazova 1, Anatoliy Ivashchenko 1, Anna Pyrkova 1, Ilya Pinsky 1, Aigul Akimniyazova 1, Siegfried Labeit 2
PMCID: PMC5452331  PMID: 28569192

Abstract

Background

Normally, one miRNA interacts with the mRNA of one gene. However, there are miRNAs that can bind to many mRNAs, and one mRNA can be the target of many miRNAs. This significantly complicates the study of the properties of miRNAs and their diagnostic and medical applications.

Results

The search of 2,750 human microRNAs (miRNAs) binding sites in 12,175 mRNAs of human genes using the MirTarget program has been completed. For the binding sites of the miR-619-5p the hybridization free energy of the bonds was equal to 100% of the maximum potential free energy. The mRNAs of 201 human genes have complete complementary binding sites of miR-619-5p in the 3’UTR (214 sites), CDS (3 sites), and 5’UTR (4 sites). The mRNAs of CATAD1, ICA1L, GK5, POLH, and PRR11 genes have six miR-619-5p binding sites, and the mRNAs of OPA3 and CYP20A1 genes have eight and ten binding sites, respectively. All of these miR-619-5p binding sites are located in the 3’UTRs. The miR-619-5p binding site in the 5’UTR of mRNA of human USP29 gene is found in the mRNAs of orthologous genes of primates. Binding sites of miR-619-5p in the coding regions of mRNAs of C8H8orf44, C8orf44, and ISY1 genes encode the WLMPVIP oligopeptide, which is present in the orthologous proteins. Binding sites of miR-619-5p in the mRNAs of transcription factor genes ZNF429 and ZNF429 encode the AHACNP oligopeptide in another reading frame. Binding sites of miR-619-5p in the 3’UTRs of all human target genes are also present in the 3’UTRs of orthologous genes of mammals. The completely complementary binding sites for miR-619-5p are conservative in the orthologous mammalian genes.

Conclusions

The majority of miR-619-5p binding sites are located in the 3’UTRs but some genes have miRNA binding sites in the 5’UTRs of mRNAs. Several genes have binding sites for miRNAs in the CDSs that are read in different open reading frames. Identical nucleotide sequences of binding sites encode different amino acids in different proteins. The binding sites of miR-619-5p in 3’UTRs, 5’UTRs and CDSs are conservative in the orthologous mammalian genes.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-017-3811-6) contains supplementary material, which is available to authorized users.

Keywords: miR-619-5p, miRNA, mRNA, Gene, Human, Orthologous genes

Background

miRNAs participate in the regulation of the expression of protein-coding genes at the post-transcriptional stage [1]. miRNAs, as a part of the RNA-induced silencing complex, bind to mRNAs and interfere with translation or promote mRNA destruction [2]. In the last two decades, properties of miRNAs and their influences on the expression of the genes involved in all key cellular processes have been established. The actions of miRNAs on the cell cycle [3], apoptosis [4], differentiation [5], and growth and development of plants [6] and animals [7] have been shown. Connections between miRNA expression and the development of various diseases have been established. miRNA concentrations change in cancer [8] and cardiovascular diseases [9]. Metabolic perturbations change miRNA concentrations in cells [10]. The aforementioned roles do not encompass all of the biological processes in which miRNAs participate, which further proves the importance of their biological functions. Despite the significant success in the study of miRNA properties, there are obstacles in identifying the target genes of miRNAs. Normally, one miRNA interacts with the mRNA of one gene. However, there are miRNAs that can bind to many mRNAs, and one mRNA can be the target of many miRNAs, which significantly complicates the study of the properties of miRNAs and their diagnostic and medical applications. There are more than 2,500 miRNAs in the human genome, and they are believed to act on 60% or more genes. Therefore, it is difficult to draw specific conclusions about the participation of miRNAs in specific biological processes, and until then the connections between the majority of miRNAs and their target genes will remain unknown. Recently, a set of unique miRNAs (umiRNA) were identified that have hundreds of target genes and bind to mRNAs with high affinity [11–14]. The binding sites of these umiRNAs are located in the 3’UTRs, CDSs, and 5’UTRs of mRNAs. Among these umiRNAs, miR-619-5p interacts with the largest number of target genes that have the greatest number of binding sites with complete complementarity of miR-619-5p and mRNAs. It is necessary to identify many miRNA binding sites in the mRNAs of these genes for the control of gene expression. Furthermore, it is important to control the expression of the corresponding gene complexes that are functionally associated with miRNAs. Therefore, we have studied a unique miR-619-5p that binds to the mRNAs of several hundred human and orthologous genes.

Methods

The nucleotide sequences of mRNAs of human genes (Homo sapience – Hsa) and orthologous genes (Bos mutus - The wild yak (Bmu), Callithrix jacchus – The common marmoset (Cja), Camelus dromedarius – Arabian camel (Cdr), Camelus ferus – The wild Bactrian camel (Cfe), Chlorocebus sabaeus – The green monkey (Csa), Colobus angolensis palliatus – The Angola colobus (Can), Equus caballus - The horse (Eca), Gorilla gorilla - The western gorilla (Ggo), Macaca fascicularis – The crab-eating macaque (Mfa), Macaca mulatta – The rhesus macaque (Mmu), Macaca nemestrina - Pig-tailed macaque (Mne), Mandrillus leucophaeus – The drill (Mle), Nomascus leucogenys - The northern white-cheeked gibbon (Nle), Ovis aries – The sheep (Oar), Pan paniscus - Bonobos (Ppa), Pan troglodytes – The common chimpanzee (Ptr), Papio anubis – The olive baboon (Pan), Pongo abelii - The Sumatran orangutan (Pab), Rhinopithecus roxellana – The golden snub-nosed monkey (Rro)) were downloaded from NCBI GenBank (http://www.ncbi.nlm.nih.gov) [15] in FASTA format using Lextractor002 script [11]. Nucleotide sequences of human mature miR-619-5p (GCUGGGAUUACAGGCAUGAGCC) were downloaded from the miRBase database (http://mirbase.org) [16]. The miR-619-5p binding sites in the 5’-untranslated regions (5’UTRs), the coding domain sequences (CDSs) and the 3’-untranslated regions (3’UTRs) of several genes were predicted using the MirTarget program [12]. This program defines the features of binding: a) the localization of miRNA binding sites in the 5’UTRs, the CDSs and the 3’UTRs of the mRNAs; b) the free energy of hybridization (∆G, kJ/mole). The ratio ΔG/ΔGm (%) was determined for each site (ΔGm equals the free energy of miRNA binding with its perfect complementary nucleotide sequence).

Results

The search of 2,750 human microRNAs (miRNAs) binding sites in 12,175 mRNAs of human genes using the MirTarget program has been completed. The mRNAs have different miRNA binding site origins, lengths, quantities, and properties. The list of miR-619-5p target genes and the positions of binding sites are outlined in Table 1. miR-619-5p is 22 nucleotides in length and is coded by an intron of the slingshot protein phosphatase 1 (SSH1) gene, which is located on chromosome 12 [17, 18]. mRNAs of 201 genes have complete complementary binding sites for miR-619-5p (ΔG/ΔGm = 100%). Therefore, the energy of interaction of miR-619-5p with mRNA of all the genes listed in the table is the same and equal to ΔG = −121 kJ/mole.

Table 1.

Positions of miR-619-5p binding sites and disease or function of target genes

Gene Site, nt Disease or function PMID Gene Site, nt Disease or function PMID
ACSL6 4639 prostate cancer 19064571 MRPS25 1609 uncharacterized 26302410
ADAL 2041 proliferation 23645737 MSH3 4139 carcinogenesis 24934723
ADAM17 3466 breast cancer 22967992 NANOS1 3219 retinoblastoma 25100735
AGMAT 2207 renal carcinoma 14648699 NCMAP 2259 uncharacterized
AK1 1449 hypertension 23863634 NDUFAF7 1697 leukemia 24292274
AKT2 4571 neuroblastoma 23468863 NDUFC2 1646 colon cancer 25804238
ALDH3A2 2617 detoxification 9829906 NLN 4215 Parkinson’s D. 25378390
ANKRD16 2165 breast cancer 20453838 NRIP2 2075 atopic asthma 17075290
AP5B1 4316 differentiation 15146197 NSL1 3063 kinetochore-protein 16585270
ARGFX 2642 development 20565723 NXPE3 7447 hepatocarcinoma 26883180
ARHGEF39 1307 tumorogenesis 22327280 OPTN 2332 glaucoma 26302410
ARL11 1033 tumorogenesis 18337727 PAG1 8156 prostatic cancer 21092590
ATCAY 2991 schizophrenia 19165527 PAQR5 4439 ovarian cancer 21761364
ATP1A2 4410 tumorogenesis 23474907 PARK2 3729 Parkinson’s D. 26860075
BCL2L15 2650 apoptosis 16690252 PBLD 2077 hepatocarcinoma 26594798
BPNT1 1128 ovarian cancer 20628624 PCGF5 5089 Alzheimer’s D. 16385451
C15orf40 523 uncharacterized PCSK5 8613 tumorogenesis 21094132
C17orf75 2895 uncharacterized PDAP1 1926 proliferation 23555679
C17orf75 3672 PDCD4 3221 tumorogenesis 26871813
C21orf58 2668 uncharacterized 11707072 PEX2 3056 cerebellar ataxia 21392394
C4orf19 2068 uncharacterized PGPEP1 1476 liver cirrhosis 25687677
C6orf170 4113 uncharacterized 20159594 PIK3R2 3345 tumorogenesis 26677064
C8orf44 336** uncharacterized PNPLA1 1991 childhood obesity 19390624
C8orf44 1626 PODNL1 1876 uncharacterized 12477932
C9orf85 871 uncharacterized POFUT1 4679 hepatocarcinoma 27003260
CACNB2 4301 hypertension 25966706 POLH 5550 ovarian cancer 25831546
CACNG8 3218 cardiomyopathy 26710323 PPM1K 2192 diabetes mellitus 23446828
CACNG8 5006 PPP1R12B 5156 childhood asthma 23640410
CACNG8 7535 PRRG4 998 Parkinson’s D 19772629
CALHM1 2896 Alzheimer’s D. 26944452 PSMB2 2925 proteolysis 21660142
CCBE1 3321 ovarian cancer 19935792 PTCD3 4116 osteosarcoma 19427859
CCDC114 261* dyskinesia 23506398 PTK6 2233 tumorogenesis 27311570
CD109 6841 bladder cancer 20946523 QRFPR 1949 metabolic S. 16648250
CD36 4042 atherosclerosis 16515687 RAB11FIP1 4928 cell transport 26790954
CD68 1398 carcinomas 21113139 RAB3IP 3975 tumorogenesis 12007189
CDAN1 4296 erythropoiesis 19336738 7022
CDHR3 4878 asthma 25848009 RAB7L1 1693 Parkinson’s D. 26914237
CEP68 4394 cervical cancer 17570516 RBBP9 1818 tumorogenesis 21933118
CHST5 2946 colon carcinoma 12107080 RGS3 205* cardiovascular D. 24375609
CHST6 2979 dystrophy 20539220 RPS6KA6 7136 tumorogenesis 26732474
CHST6 3876 SCN11A 5871 neurophaty 25791876
CIAO1 2416 tumorogenesis 9556563 SEPT11 4033 hepatocarcinoma 20419844
CIAO1 3814 SEPT14 1575 Parkinson’s D 27115672
CLEC19A 1747 lectin 12975309 SGTB 3142 lymphopoesis 2158125
CLTC 7006 pancreatic cancer 23228632 SH3GLB1 4856 prostate cancer 27748942
CORO2A 2227 colon cancer 23490283 SLC15A2 4333 hepatocarcinoma 25965825
COX18 1264 tumorogenesis 20819778 SLC17A5 2389 cardiovascular D 27872510
CPM 2698 renal carcinoma 23172796 SLC26A2 5066 colorectal cancer 23840040
CPM 4996 SLC26A4 4210 hearing loss 27729126
CPT2 2557 sudden death 21641254 SLC28A2 2196 chronic hepatitis C 23195617
CYB5RL 3426 transcription 16344560 SLC7A11 6304 tumorogenesis 26729415
CYP20A1 2539 tumorogenesis 15191668 SLC7A14 8487 breast cancer 20379614
CYP20A1 4709 SNX22 902 liver-disease 21988832
CYP27C1 3823 self-rated health 20707712 SOWAHC 3417 retrotransposon 22234889
CYP2W1 2176 colorectal cancer 22993331 SPATA13 5020 colorectal cancer 17599059
DAP3 1842 breast cancer 22287761 SPATA5 5648 microcephaly 26299366
DCAF10 3305 lung cancer 28336923 SPATS2 3332 breast cancer 20379614
DCAF10 4559 SPN 5287 tumorogenesis 25551301
DCLRE1C 2966 Omenn syndrome 25981738 STAC2 2241 inherited ataxias 16713569
DDOST 1782 hyperglycemia 22305527 SYNJ2BP 1298 breast cancer 19349195
DHODH 1709 melanoma 21430780 SYNJ2BP 4175
DHRS9 1281* tumorogenesis 26254099 TCEB1 1964 tumorogenesis 23083832
DNAL1 4925 dyskinesia 15845866 TIGD6 3439 uncharacterized
DSCR6 1706 Down syndrome 10814524 TMEM156 1593 uncharacterized
ERBB3 5104 tumorogenesis 26689995 TMEM19 3510 uncharacterized
FADS6 1777 liver disease 21988832, TMEM213 875 uncharacterized
FAM161A 2785 retinal disease 25749990 TMEM214 1190 uncharacterized
FAM227A 4981 cancer 26759717 TMEM50B 1026 uncharacterized
FAM84B 3626 tumorogenesis 25980316 TMEM56 1243 nicotine dependence 20379614
FBLIM1 2126 breast cancer, 23645746 TMF1 4736 prostate cancer 19330832
FBXL22 1411 cardiomyopathy 24324551 TMOD2 7816 bladder cancer 15095301
FBXO27 1535 leukemia 126433 TNFRSF10A 1621 cancer 27780136
FGD4 7619 cancer 22589722 TNFRSF10D 1532 cancer 26542757
FKBP14 1515 ovarian cancer 27931282 TOP3A 3814 leukaemia 22050635
FKBP14 2129 TPRG1L 1754 uncharacterized
FKBP5 7114 schizophrenia 25522420 TRIM72 1885 ischemia 26790476
FXN 3288 metabolic disease 26717909 TRPM7 8079 neuroblastoma 27402209
GDPD1 1559 phosphodiesterase 18991142 TRPM7 8221 carcinoma 26779625
GEMIN8 2172 neuropathy 16434402 TXNDC15 2460 thrombosis 21642008
GGT6 1956 ovarian cancer 25356737 TYW5 3692 schizophrenia 23974872
GK5 3808 glioblastoma 25936394 UACA 6120 lung cancer 22407486
GK5 6355 glioblastoma 25936394 UACA 6120 thyroid diseases 15358194
GLB1L 2224 phosphatase 21382349 UBIAD1 2881 cancer 23759948
GOLGA3 7240 immune disease 17711851 UBXN2A 1665 colon cancer 24625977
GP2 1877 crohn disease 22891285 UPK1B 1513 cancer 16354592,
GPR65 3309 tumorogenesis 24152439 UQCRB 1269 colorectal cancer 22545919
GPR65 3309 immune diseases 15665078 USP29 2* protease 10958632
GPR82 2664 uncharacterized VHL 3764 tumorogenesis 27460078
GPRIN2 6676 schizophrenia 27244233 VHL 3898
GTPBP10 1873 prostate cancer 27409348 VWA2 3366 colon cancer 15580307
H6PD 5754 tumorogenesis 15221007 WDR73 1736 microcephaly 25466283
HM13 1745 glioblastoma 28198167 XIAP 5681 ovarian cancer 26779627
IFIT3 1864 pancreatic cancer 25650658 YAE1D1 1548 oral cancer 23318452
ISY1 686** uncharacterized ZBTB24 4842 hepatocarcinoma 27730394
IYD 1658 hypothyroidism. 18765512 ZC3H12D 2812 Acute lung injury 26059755
KIAA1456 2536 colorectal cancer 24743840 ZDHHC20 3390 tumorogenesis 20334580
KIF11 3598 tumorogenesis 28011472 ZFP30 3463 hypertension 19851296
KLHL23 2570 tumorogenesis 23676014 ZNF114 1827 transcription factor 8467795
KPNA1 5711 breast cancer 26052702 ZNF197 3446 thyroid cancer 12682018
KREMEN1 2199 schizophrenia 20153141 ZNF320 5534 glioblastoma 11536051
KREMEN1 2792 schizophrenia 20153141 ZNF429 2081** transcription factor 7865130
LAX1 2057 uncharacterized ZNF445 8820 transcription factor 16368201
LILRA6 2201 tumorogenesis 26769854 ZNF461 3087 transcription factor 15004467
LIMD1 5735 breast cancer 27656835 ZNF549 3736 transcription factor 16344560
LIMS1 3931 cancer 27590440 ZNF557 4791 transcription factor 15851553
LMOD3 3224 myopathy 25250574 ZNF626 4620 liver diseases 18255255
LMOD3 3993 Alzheimer’s D 22881374 ZNF667 3240 transcription factor 17397802
METTL6 1188 breast cancer 25151356 ZNF716 2799 cardiovascular D 24376456
MR1 3664 hepatocarcinoma 26823810 ZNF780B 5415 transcription factor 15057824
MREG 1540 pulmonary D 20463177 ZNF84 4920 transcription factor 11856868
ZNF841 3422 transcription factor 24280104
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Notes: * - 5’UTR, **- CDS; others – 3’UTR, D - disease

The mRNAs of 201 human genes have complete complementary binding sites of miR-619-5p in the 3’UTR (214 sites), CDS (3 sites), and 5’UTR (4 sites). The mRNAs of 27 genes have four binding sites, seven genes have five binding sites, and CATAD1, ICA1L, GK5, POLH, and PRR11 genes have six miR-619-5p binding sites. The mRNAs of OPA3 and CYP20A1 genes have eight and ten binding sites, respectively. All of these sites are located in the 3’UTRs of mRNAs.

The target genes of the miR-619-5p carry out one or more different functions and are involved in the development of various diseases (Table 1).

The mRNAs of the C17orf75, C8orf44, CIAO1, CPM, CYP20A1, DCAF10, FKBP14, RAB3IP, SYNJ2BP, VHL genes have two complete complementary binding sites for miR-619-5p, and the mRNA of the CACNG8 gene has three such binding sites. This indicates a stronger dependence of the expression of these genes on miR-619-5p.

One of the methods to establish the credibility of the presence of miRNA binding site in the mRNA is to verify this site in the mRNAs of orthologous genes. In finding the miRNA binding sites raises the question of the level of reliability of the found sites. One effective way to establish the credibility of the binding sites is to establish binding sites in the orthologous genes and the identification of orthologous miRNA. Location of binding site in the protein coding region facilitates its conservation in evolution, especially if the corresponding oligopeptide plays an important role in the function of the protein. miR-619-5p binding sites with complete complementarity (ΔG/ΔGm is 100%) to the mRNAs of the four genes are located in the 5’UTRs (Table 2).

Table 2.

Variation of positions and nucleotide sequences of miR-619-5p binding sites in the 5’UTRs of mRNAs of mammal genes

Species Gene Position
of site, nt		 Nucleotide sequence
Hsa CCDC114 261 GCAUGCUGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Hsa DHRS9 1281 GCGCGGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Hsa RGS3 205 GCGCAGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Ptr RGS3 1 GCGCAGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Nle RGS3 205 GCACGGUGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Hsa USP29 2 CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Pab USP29 52 CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Nle USP29 52 CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Mle USP29 47 CUGGCCAGGCUCAUGCCUGUAAUCCCAGCACUUUGG
Can USP29 98 CUGGCCAGGCUCAUGCCUGUAAUCCCAGCAUUUUGG
Ggo USP29 100 CUGGCCAGGCUCAUGCCUGUAAUUCCAGCACUUUGG
Rro USP29 52 CUGGCCAGGCUCAUGCCUGUAAUCGCAGCACUUUGG
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Notes: In the table 2-5 the bold type indicates the binding site of miR-619-5p

Before the 5’ end and after the 3’ end of miR-619-5p binding site, nucleotides are not homologous. The mRNAs of RGS3 and USP29 orthologous genes have binding sites in H. sapiens, N. leucogenys, P. abelii, M. leucophaeus, C. angolensis palliatus, G. gorilla, and R. roxellana.

miR-619-5p has two binding sites in the 5’UTRs of mRNAs of ANAPC16, CYB5D2, and PRR5 and three binding sites in the mRNA of DNASE1.

mRNAs of some genes have binding sites for miR-619-5p within their 5’UTRs and 3’UTRs or CDSs and 3’UTRs. For example, ATAD3C, C14orf182, and CYB5RL have miR-619-5p binding sites in the 5’UTRs and 3’UTRs, and C8orf44, ISY1, and ZNF714 have miR-619-5p binding sites in the CDSs and 3’UTRs.

The nucleotide sequences of miR-619-5p binding sites are located in the CDSs of the C8orf44, C8H8orf44, ISY1, ZNF429, and ZNF714 genes and encode the following oligopeptides (Table 3). C8H8orf44, C8orf44, and ISY1 genes encode the WLMPVIP oligopeptide, which is also present in the orthologous proteins of P. abelii, P. anubis, P. paniscus, and P. troglodytes. The mRNA of transcription factor ZNF429 and ZNF429 genes binding sites are encoded the AHACNP oligopeptide in the another reading frame. The first two oligopeptides are encoded in one open reading frame (ORF) and the amino acid sequences are highly conserved. The homologous oligonucleotide of the miR-619-5p binding site in the mRNA of ZNF714 gene codes for an oligopeptide in a different ORF.

Table 3.

Variation of amino acid sequences coding in miR-619-5p binding sites in the mRNAs of orthologous genes

Species Gene Amino acid sequence
Hsa C8orf44 HWKGRARWLMPVIPALWEAKA
Hsa C8H8orf44 HWKGRARWLMPVIPALWEAKA
Pab C8H8orf44 HWKGWARWLTPVIPALWEAKA
Pan C8H8orf44 HWKGRARWLMPAIPALWEAKX
Ppa C8H8orf44 HWKGRAQWLTPVIPALWEAKA
Ptr C8H8orf44 HWKGRAQWLTPVIPALWEAKA
Hsa ISY1 EKERQVRWLMPVIPALWEAEA
Hsa ZNF714 KIQQGMVAHACNPNTLRGLGE
Ggo ZNF714 KIQQGMVAHACNPNTLRGLGE
Ptr ZNF714 KIQQGMVAHACNPNTXRGLGE
Ppa ZNF714 KIQQGMVAHACNPNTLRGLGE
Hsa ZNF429 IHRMGVVAHACNPSTLGGRGG
Mfa ZNF429 IHRLGVVAHACNPSTLGGRGG
Mmu ZNF429 IHRLGVVAHACNPSTLGGRGG
Mne ZNF429 IHRLGVVAHACNPSTLGGRGG
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The presence of miR-619-5p binding sites in the CDSs of five genes with different functions and the evolutionary conservation of these sites signify the role of miRNA in the regulation of the expression of these genes. The nucleotide sequences of specific regions of mRNAs of C8H8orf44, C8orf44, ISY1, ZNF429, and ZNF714 genes that contain miR-619-5p binding sites in the CDSs are homologous among themselves and to the binding sites located in the 5’UTRs and 3’UTRs.

The miRNA binding sites in the coding region, as opposed to the 3’UTR and 5’UTR, clearly demonstrate the relationship between miRNA and mRNA by their conserved amino acid sequences in orthologous proteins. miRNA binding site can be translated by two open reading frames that encode WLTPVIPA and AHACNPS oligopeptides. In the third reading frame, the miR-619-5p binding site has a stop codon. However, in the genes studied, no such sequence was found. In the absence of complete complementarity between miR-619-5p and its binding site, miR-619-5p uses a site containing the corresponding mutation in the CDS for the regulation of gene expression. Thus, a single miRNA binding site in the mRNA of various genes may correspond to three different oligopeptides. Generally, one out of these three oligopeptides is present in the proteins encoded by the orthologous genes.

ISY1 orthologous genes in H. sapiens, P. troglodytes, and N. leucogenys encode a protein containing QVRWLMPVIPALWEAEAGGSQA oligopeptide sequence (Table 4).

Table 4.

Amino acid sequences coding in miR-619-5p binding sites in the mRNA of ISY1 gene of orthologous genes

Species Amino acid sequence
Hsa PGVRELFEKERQVRWLMPVIPALWEAEAGGSQALPPPRKTRAELMKA
Ptr PGVRELFEKERQVRWLMPVIPALWEAEAGGSQALPPPRKTRAELMKA
Nle PGVRELFEKERQARWLTPVIPALWEAEAGGSQALPPPRKTRAELMKA
Hsa* PGVRELFEKEP----------------------LPPPRKTRAELMKA
Bmu PGVRELFEKEP----------------------LPPPRKTRAELMKA
Cdr PGVRELFEKEP----------------------LPPPRKTRAELMKA
Cfa PGVRELFEKEP----------------------LPPPRKTRAELMKA
Cja PGVRELFEKEP----------------------LPPPRKTRAELMKA
Eca PGVRELFEKEP----------------------LPPPRKTRAELMKA
Ggg PGVRELFEKEP----------------------LPPPRKTRAELMKA
Mmu PGVRELFEKEP----------------------LPPPRKTRAELMKA
Nle PGVRELFEKEP----------------------LPPPRKTRAELMKA
Oar PGVRELFEKEP----------------------LPPPRKTRAELMKA
Pab PGVRELFEKEP----------------------LPPPRKTRAELMKA
Ppa PGVRELFEKEP----------------------LPPPRKTRAELMKA
Rro PGVRELFEKEP----------------------LPPPRKTRAELMKA
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* RAB43 - human ISY1 paralog gene

However, the RAB43 gene, which is paralogous to human ISY1, lacks the nucleotide sequence encoding the QVRWLMPVIPALWEAEAGGSQA oligopeptide. Additionally, ISY1 gene in the genomes of other animals also lacks the nucleotide sequence encoding this oligopeptide (Table 4).

Nucleotide sequences of miR-619-5p binding sites in the mRNAs of ADAM17, ALDH3A2, and ARL11 orthologous genes are shown in Table 5.

Table 5.

Variation of nucleotide sequences of miR-619-5p binding sites in the 3’UTR of mRNAs of ADAM17, ALDH3A2, and ARL11 of orthologs

Species Gene Position, nt Nucleotide sequence
Hsa ADAM17 3466 TGGGAGTGGTGGCTCATGCCTGTAATCCCAGCACTTGGAGAGG
Cat ADAM17 3485 GGGGCGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Mmul ADAM17 3491 GGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Mne ADAM17 3438 GGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Ptr ADAM17 3449 TGGGAGTGGTGGCTCATGCCTGTAATCCCAGCACTTGGAGAGG
Rro ADAM17 3425 GGGGCGCGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Hsa ALDH3A2 2617 CGGGCGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Cja ALDH3A2 3444 CGGGCGTGGTGGCTCATGCCTGTAATCCCAGCACTTTAGGAGG
Ggo ALDH3A2 2712 CGGGCGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Mmul ALDH3A2 2509 CGGACATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Mne ALDH3A2 2504 CGGACATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Nle ALDH3A2 2714 TGGTCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Pab ALDH3A2 2297 TGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Ppa ALDH3A2 2715 CGGGCATGGTGGCTCATGTCTGTAATCCCAGCACTTTGGGAGG
Ptr ALDH3A2 2711 CGGGCATGGTGGCTCATGTCTGTAATCCCAGCACTTTGGGAGG
Rro ALDH3A2 2727 CGGACGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG
Hsa ARL11 1033 TTGGCCCGGTGGCTCATGCCTGTAATCCCAGCACTGTGGGAGA
Cat ARL11 1642 CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG
Mfa ARL11 1698 CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG
Mmul ARL11 1747 CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG
Mne ARL11 1024 TTGGCACGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGA
Mne ARL11 1471 CAGATGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGTGG
Ptr ARL11 1353 CGGGCATGGTGGCTCATGTCTGTAATCCCAGCACTTTGGGAGG
Rro ARL11 1254 CAGGTGCAGTGGCTCATGCCTGTAATCCCAGCACTTTGGGCGG
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These orthologous genes are characterized by highly conserved nucleotide sequence GGCTCATGCCTGTAATCCCAGC of miR-619-5p binding sites. This shows that the interaction of miR-619-5p with mRNAs of these genes is conserved during evolution. Some of the human miR-619-5p target genes and their corresponding orthologous genes have two miR-619-5p binding sites in their mRNAs.

Table 6 shows the nucleotide sequences of two miR-619-5p binding sites in the 3’UTR of mRNAs of ERBB3, FBLIM1, and FKBP14 orthologous genes.

Table 6.

Variation of nucleotide sequences of two miR-619-5p binding sites in the 3’UTR of mRNAs of ERBB3, FBLIM1, and FKBP14 of orthologs

Species Gene Position, nt Nucleotide sequence
Hsa ERBB3 4950 CGGGCATGGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAG
Hsa ERBB3 5104 TGGGTGCAGTGGCTCATGCCTGTAATCCCAGCCAGCACTTTG
Csa ERBB3 4989 CGGGCATGGTGGCTCATGCCTGTAATCCTAGCACTTTGGGAG
Csa ERBB3 5149 TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCACTTTGGGAG
Mfa ERBB3 5114 TGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG
Mfa ERBB3 5269 TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG
Mmu ERBB3 5114 TGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG
Mmu ERBB3 5269 TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG
Mne ERBB3 5112 CGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG
Mne ERBB3 5267 TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG
Pan ERBB3 5106 CGGGCATGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAG
Pan ERBB3 5274 TGGGCGCTGTGGCTCATGCCTGCAGTCCCAGCACTTTGGGAG
Ptr ERBB3 5105 CGGGCATGGTGGCTCATGCCTGTAATCTCAGCACTTTGGGAG
Ptr ERBB3 5243 TGGGTGCAGTGGCTCATGCCTGTAATCCCAGCCAGCACTTTG
Mne FBLIM1 1938 TGGGCGTGGTGGCTCATGCCTGTAATCCCTGCACTTTGGGAG
Mne FBLIM1 5267 TGGGCGCTGTGGCTCATGCCTGCAATCCCAGCCCTTTGGGAG
Pab FKBP14 1514 CAGGCACGGTGGCTCACGCCTGTAATCCCAGCACTTCGGGAG
Pab FKBP14 2128 TGGGTGTGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGGG
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Notes: The black type indicates the binding site of miR-619-5p

Table 7 shows the degree of conservation of miR-619-5p binding sites in the 201 mRNAs of target genes. All mRNAs with complete complementarity to miR-619-5p binding sites (ΔG/ΔGm is 100%) were divided into four groups, and the frequency of occurrence of nucleotides was determined in each group. The results suggest that miR-619-5p binding sites are highly conserved. The binding site GGCTCATGCCTGTAATCCCAGC does not change and in each of the four gene groups the observed variability of nucleotides on the right and left is high.

Table 7.

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites (See Additional file 1, 2, 3 and 4)

graphic file with name 12864_2017_3811_Tab7_HTML.jpg

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Discussion

Here we have identified many miRNAs binding sites in the mRNAs of 201 human genes which indicates that umiRNAs act as coordinators of gene expression by participating in many biological processes. Previous studies have shown the influences of miRNAs on the expression of genes that encode the transcription factors [19, 20] and on the expression of proteins that participate in the cellular cycle [3, 21–23], apoptosis [4, 24–26], and stress responses [27]. It was shown the role of the mir-619-5p in the regulation of different pathological processes [28]. It was investigated the correlations between the expression of MALAT1 and miR-619-5p, in addition to the association between the clinicopathological features and survival outcomes of patients with stage II and III colorectal cancer tumors [28]. It was observed, that hsa-miR-619-5p and hsa-miR-1184 microRNA expression significantly increased in prostatic cancer. MicroRNA-gene-net analysis indicated that miR-619-5p and other some miRNAs had the most important and extensive regulatory function for Qi-stagnation syndromes and Qi-deficiency syndromes in coronary heart disease [29].

One or several umiRNAs regulating the expression of hundreds of genes can create a system of interconnected processes in cells and organisms. Such role of these umiRNAs is possible because they circulate in the blood and have access to nearly all cells of an organism [30–32]. Our results provide the basis for studying the systemic roles of unique and normal miRNAs in the regulation of gene expression in human cells. The expression of many target genes is regulated by umiRNAs does not allow individual mRNAs of target genes to be expressed in more degree than others. The greater expression of one mRNA, the larger number of umiRNAs bind to this mRNA. This allows one umiRNA to maintain a certain balance of expression of the corresponding target genes. If umiRNA expression changes, such system is vulnerable. This will cause the development of pathology in the cell, tissue or body.

Conclusions

The majority of miR-619-5p binding sites are located in the 3’UTRs of mRNAs of target genes. Some genes have miRNA binding sites in the 5’UTRs of mRNAs. It is necessary to maintain nucleotide sequences of the binding site of umiRNA in the CDSs of several genes. Different genes have binding sites for miRNAs that are read in different open reading frames. Therefore, identical nucleotide sequences encode different amino acids in different proteins. In encoded proteins, these sites encode conservative oligopeptides. The binding sites of miR-619-5p in 3’UTRs, 5’UTRs and CDSs are conservative in the orthologous mammalian genes.

Additional files

Additional file 1: Figure S1. (218.1KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from CSL6 to COX18 (Conservative binding sites are in bold) (PDF 218 kb)

Additional file 2: Figure S2. (106.5KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from GK5 to HM13 (Conservative binding sites are in bold) (PDF 106 kb)

Additional file 3: Figure S3. (139.3KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from IFIT3 to SLC26A4 (Conservative binding sites are in bold) (PDF 139 kb)

Additional file 4: Figure S4. (151.2KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from LC28A2 to ZNF841 (Conservative binding sites are in bold). The data given in the Additional files 1, 2, 3 and 4 demonstrate the variability of the nucleotides before and after the binding sites of miR-619-5p, which is shown in the Weblogo schemes in the table 8. (PDF 151 kb)

Acknowledgements

We thank Leducq foundation and the European Union project «Muscle Stress Relief». Also we thank PhD Berillo O. for her help in the collection of data.

Funding

This study was supported by a grant (N0491/ГФ4) from the Ministry of Education and Science, Kazakhstan Republic, SRI of Biology and Biotechnology Problems, al-Farabi Kazakh National University, and Institute for Anesthesiology and Intensive Operative Care Medical Faculty Mannheim, Mannheim, Germany.

Availability of data and materials

The data sets supporting the results of this article are included within the article and its additional files and publicly available.

Authors’ contributions

SA, RN and AI conceived of the study and drafted the manuscript. SA, RN, AI, SL, AP, IP and AA made substantial contributions to acquisition of data, to interpretation and modification of the data. All authors involved in drafting the manuscript, read and approved the final version of the manuscript.

Competing interests

The authors declares that they have no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Abbreviations

CDSs

Coding domain sequences

miRNAs

Micrornas

ORF

Open reading frame

Umirna

Unique miRNA

Footnotes

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-017-3811-6) contains supplementary material, which is available to authorized users.

Contributor Information

Shara Atambayeva, Email: atambayevashara@gmail.com.

Raigul Niyazova, Email: Raigul.Nyiyazova@kaznu.kz.

Anatoliy Ivashchenko, Email: a.iavashchenko@gmail.com.

Anna Pyrkova, Email: Anna.Pyrkova@kaznu.kz.

Ilya Pinsky, Email: ilya.pinskyi@mail.ru.

Aigul Akimniyazova, Email: akimniyazova@gmail.com.

Siegfried Labeit, Email: labeit@embl.de.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Additional file 1: Figure S1. (218.1KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from CSL6 to COX18 (Conservative binding sites are in bold) (PDF 218 kb)

Additional file 2: Figure S2. (106.5KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from GK5 to HM13 (Conservative binding sites are in bold) (PDF 106 kb)

Additional file 3: Figure S3. (139.3KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from IFIT3 to SLC26A4 (Conservative binding sites are in bold) (PDF 139 kb)

Additional file 4: Figure S4. (151.2KB, pdf)

Variation of nucleotide sequences of mRNA region with miR-619-5p binding sites of genes from LC28A2 to ZNF841 (Conservative binding sites are in bold). The data given in the Additional files 1, 2, 3 and 4 demonstrate the variability of the nucleotides before and after the binding sites of miR-619-5p, which is shown in the Weblogo schemes in the table 8. (PDF 151 kb)

Data Availability Statement

The data sets supporting the results of this article are included within the article and its additional files and publicly available.

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