Table 1.
Functions of Chromodomain-containing Proteins
| Proteina | Functions in mammalsb | Functional Contributions of CDs | Human Disease Relevance |
|---|---|---|---|
| CBX1 (HP1β) Refs (19, 58, 71, 78-83) | (All HP1 isoforms) Heterochromatin formation and transcriptional repression; interacts with SUV39H1; interacts with KAP1, DNMT1 for euchromatic gene silencing; recruited to UV-induced DNA damage and double strand breaks; dynamic exchange with other HP1 isoforms for maintaining stable heterochromatic state; cell cycle-dependent localization. | (All HP1 isoforms) H3K9me binding, ejected by H3S10ph during M phase; possible localization by binding to H1.4K26me, ejected by H1.4S27ph; binds H3K23me1; multimerization mediated by CD for heterochromatin spreading (yeast). (CBX1-specific) T51 phosphorylation with mobilization releases HP1β from chromatin. | Low expression associated with melanoma progression. |
| CBX3 (HP1γ) Ref (19, 58, 79, 81-84) | See CBX1. (CBX3-specific) Regulation of cell differentiation. | See CBX1. | |
| CBX5 (HP1α) Refs (19, 58, 79, 81-83, 85, 86) | See CBX1. (CBX5-specific) Interacts with linker H1; neuronal terminal differentiation; interacts with BRG1 to negatively regulate SWI/SNF chromatin remodeling. | See CBX1. | Alters invasive potential of breast cancer cells requiring HP1 dimerization but not PXVXL interaction. |
| CBX2 (Pc1/M33) Refs (5, 35, 72, 87-89) | (All Pc isoforms) Chromatin recruitment module of Polycomb Repressive Complex 1, interacts with Ring1B; different isoforms have distinct localization and mobility patterns within chromatin; enriched on Xi (except CBX4). (CBX2-specific) Repression of ovarian development in XY gonads possibly by regulation of SRY or WT1. | (All Pc isoforms) H3K27me reader of PRC1. Differential affinities for H3K9me, H3K27me and RNA (except CBX2 cannot bind RNA). (CBX2-specific) S42 phosphorylation leads to minor changes in affinity for H3K9me and H3K27me. | Overexpression in diploid breast carcinoma. |
| CBX4 (Pc2) Refs (5, 35, 87, 90, 91) | See CBX2. (CBX4-specific) Target of SENP2 desumoylation enzyme in cardiac development; SUMO E3 ligase; tumor suppressor. | See CBX2. | |
| CBX6 Refs (5, 35, 87, 92) | See CBX2. (CBX6-specific) Distinct distribution and mobility properties, weaker interaction with endogenous Ring1B and Polycomb group target genes suggest a different role from other Pc isoforms, although chromobox can still bind Ring1B. | Binds H3K27me3 weakly. | |
| CBX7 Refs (5, 93) | See CBX2. (CBX7-specific) Cellular lifespan extension and senescence; regulation of Ink4a/ARF locus; binds Xist RNA in X inactivation. | See CBX2. (CBX7-specific) Association with RNA. | Up- or downregulation in several cancers. Marker of poor prognosis. Initiates repression of genes silenced with cancer-specific DNA hypermethylation. |
| CBX8 (Pc3) Refs (5, 35, 94) | See CBX2. (CBX8-specific) Regulation of Ink4a/ARF locus, dependent on Bmi1. | See CBX2. (CBX8-specific) Necessary for nuclear localization. | |
| CDY1/2 Refs (6, 7, 95) | HAT with preference for H4, H4 hyperacetylation during spermatogenesis; colocalizes with CBX1/HP1b. | Binds H3K9me1/2/3, H1.4K26me3, H3K27me2/3, G9aK185me1/3. | Marker for various male sex chromosomal abnormalities. |
| CDYL1 (CDYL) Refs (95-97) | Spermatogenesis; transcriptional co-repressor, binds HDACs and CoA; HAT activity in vitro; REST corepressor that interacts with REST and G9a. | Methylation by G9a outside CD abolishes H3K9me3 interaction. | |
| CDYL2 Refs (7, 96) | Spermatogenesis. | Binds H3K9me1/2/3, H1.4K26me3, H3K27me2/3, G9aK185me1/3. | |
| MPP8 Refs (98) | Probable involvement in M-phase functions, phosphorylation-dependent; localized to nucleus during interphase, throughout the cell during M phase. | Binds H3K4me3; H3K9me2/3 binding leads to recruitment of E-cadherin, then DNMT3A. | Up-regulated in carcinomas, function in tumor progression, repress tumor suppressor gene expression. |
| SUV39H1 (KMT1A) Refs (99-101) | HMT for H3K9me3 to establish constitutive pericentric heterochromatin; S-phase gene silencing during differentiation. | Binding to H3K9me essential for spreading of heterochromatin (yeast Clr4). | ERalpha transcription in breast cancer; RB1 mutants found in human cancers can't bind SUV39H1; higher expression in colorectal tumors; lymphomagenesis. |
| SUV39H2 (KMT1B) Refs (100, 102) | Formation of pericentric heterochromatin via H3K9 trimethylation. | SNP in 3’-UTR associated with increase in lung cancer risk. | |
| CHD1 Refs (10, 103-105) | Regulation of RNA polymerase II transcription; ATP-dependent chromatin assembly; pluripotency of ESCs. | Tandem CDs recognize H3K4me3. Acidic linker helix gates DNA access to ATPase motor. | |
| CHD2 Refs (11, 106, 107) | Development, hematopoiesis, tumor suppression; kidney function. | Binds H3K4me3 more weakly than CHD1, possibly gated by phosphorylation. | Differential expression in urinary bladder cancer; translocation disruption results in scoliosis. |
| CHD3 (Mi-2a) Refs (10, 46, 108-110) | NuRD HDAC and repressive complex; transcriptional repression or co-activator of c-Myb. | DNA binding by Drosophila Mi-2 CDs in nucleosome binding and mobilization. | Dermatomyositis autoimmune disease resulting in autoantibodies against CHD3/4. |
| CHD4 (Mi-2b) Refs (46, 108-111) | NuRD complex; checkpoint signaling and DNA damage repair; promotes CD4 gene expression during T cell development. | See CHD3. | See CHD3. |
| CHD5 Refs (46, 112) | Tumor suppressor that controls proliferation, apoptosis and senescence via the p19ARF/p53 pathway. | See CHD3. | Downregulated through promoter hypermethylation, mutation in several types of cancer. |
| CHD6 Refs (11, 113, 114) | Interacts with Nrf2 transcription factor in cellular redox homeostasis; cell proliferation and radiosensitivity; transcription preinitiation and elongation via RNA pol II. | Possible shared coordination of methylated lysine by both CDs. | TCF4 translocation leads to mild retardation related to Pitt-Hopkins syndrome. |
| CHD7 Refs (11, 115-118) | Neural crest formation and cell motility; inner ear development; ribosomal RNA biogenesis; enhancer mediated transcription. | See CHD6. | Mutations in CHARGE and Kallmann syndromes; idiopathic scoliosis. |
| CHD8 Refs (119-122) | AR-mediated or beta catenin-mediated transcription; HOXA2 and cyclin E2 expression; interacts with CHD7; suppresses p53-mediated apoptosis. | H3K4me2 binding to both CDs similar to CHD1, possible chromatin recruitment. | Idiopathic developmental delay and cognitive impairment. |
| CHD9 Ref (11, 123) | Osteogenic cell differentiation. | See CHD6. | |
| TIP60 (KAT5) Refs (124, 125) | NuA4 HAT complex; tumor suppressor, apoptosis, DNA repair, cell cycle progression; H2A and H4 HAT, acetylation and activation of ATM. | H3K9me3 binding activates HAT, dependent on DNA damage-induced displacement of HP1b from H3K9me3. | Low levels in several cancers; prostate cancer cell proliferation; implicated in Alzheimer's disease |
| MYST1 (MOF/MOZ) Refs (126-128) | MSL H4K16 HAT complex; cell cycle, DNA repair; associates with H3K4 HMT MLL1 for transcriptional activation. | Interaction with ATM. | |
| ARID4A (RBBP1) Refs (129-131) | mSIN3 HDAC complex; binds Rb, promotes repression and growth arrest. | Leukemia suppressor gene | |
| ARID4B (RBBP1L1) Refs (130, 131) | mSIN3 HDAC complex | Molecular marker for several cancers; leukemia suppressor gene | |
| MORF4L1 (Eaf3/MRG15) Refs (132, 133) | NuA4 HAT and mSIN3 complexes; transcriptional repression, cell proliferation and aging, DNA damage repair, gene splicing. | Assembly of MAF2 complex (with MOF) and HAT activity | |
| MSL3 (MSL3L1) Refs (128, 134-136) | MSL H4K16 HAT complex; X inactivation. | Nucleic acid (RNA, ssDNA) binding. H3K36me3 binding, X chromosome gene association, MSL complex spreading to active genes in cis. | |
| SMARCC1 (BAF155) Refs (137, 138) | SWI/SNF, WINAC, BRG complexes; transcriptional activation and repression, heterochromatin formation, chromatin compaction during differentiation. | Up-regulated in prostate cancer, tumor recurrence. | |
| SMARCC2 (BAF170) Refs (138-140) | SWI/SNF, WINAC, BRG complexes; transcriptional activation and repression. | Reduced cell viability in primary chronic lymphocytic leukemia cells. Dysregulation in testicular germ cell, squamous non-small cell lung cancers. |
a
References cited are representative only. We apologize to all authors whose work are not cited due to space limitations.
b
Abbreviations: CD, chromodomain. HAT, histone acetyltransferase. HMT, histone methyltransferase. HDAC, histone deacetylase.