Atrophin Recruits HDAC1/2 and G9a to Modify Histone H3K9 and to Determine Cell Fates

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2008 May 3

PMID 18451879

Citations 44

Authors

Lei Wang

Bernard Charroux

Stephen Kerridge

Chih-Cheng Tsai

Affiliations

Soon will be listed here.

Abstract

Atrophin family proteins, including the vertebrate arginine-glutamic acid dipeptide repeats protein (RERE) and Drosophila Atrophin (Atro), constitute a new class of nuclear receptor corepressors. Both RERE and Atro share the ELM2 (EGL-27 and MTA1 homology 2) and SANT (SWI3/ADA2/N-CoR/TFIII-B) domains, which are also present in other important transcriptional cofactors. Here, we report that the SANT domain in RERE binds to the histone methyltransferase G9a, and that both the ELM2 and SANT domains orchestrate molecular events that lead to a stable methylation of histone H3-lysine 9. We establish the physiological relevance of these interactions among Atrophin, G9a, and histone deacetylases 1 and 2 in Drosophila by showing that these proteins localize to overlapping chromosomal loci, and act together to suppress wing vein and melanotic-mass formation. This study not only shows a new function of the SANT domain and establishes its connection with the ELM2 domain, but also implies that a similar strategy is used by other ELM2-SANT proteins to repress gene transcription and to exert biological effects.

Citing Articles

CircRNAs expression profile and potential roles of circRERE-PMN in pre-metastatic lungs.

Shi H, Wang Y, Chen L, Li Y, Qin Y, Lv J Front Immunol. 2024; 15:1455603.

PMID: 39253079 PMC: 11381296. DOI: 10.3389/fimmu.2024.1455603.

Functional implications of paralog genes in polyglutamine spinocerebellar ataxias.

Felicio D, du Merac T, Amorim A, Martins S Hum Genet. 2023; 142(12):1651-1676.

PMID: 37845370 PMC: 10676324. DOI: 10.1007/s00439-023-02607-4.

A potential histone-chaperone activity for the MIER1 histone deacetylase complex.

Wang S, Fairall L, Pham T, Ragan T, Vashi D, Collins M Nucleic Acids Res. 2023; 51(12):6006-6019.

PMID: 37099381 PMC: 10325919. DOI: 10.1093/nar/gkad294.

Whole-genome functional characterization of RE1 silencers using a modified massively parallel reporter assay.

Mouri K, Dewey H, Castro R, Berenzy D, Kales S, Tewhey R Cell Genom. 2023; 3(1):100234.

PMID: 36777181 PMC: 9903721. DOI: 10.1016/j.xgen.2022.100234.

Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling.

George A, Lee J, Liu J, Kim S, Brooks B Dev Dyn. 2022; 252(4):495-509.

PMID: 36576487 PMC: 11528340. DOI: 10.1002/dvdy.561.

References

Shi Y, Sawada J, Sui G, Affar E, Whetstine J, Lan F . Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature. 2003; 422(6933):735-8. DOI: 10.1038/nature01550. View

Stabell M, Eskeland R, Bjorkmo M, Larsson J, Aalen R, Imhof A . The Drosophila G9a gene encodes a multi-catalytic histone methyltransferase required for normal development. Nucleic Acids Res. 2006; 34(16):4609-21. PMC: 1636376. DOI: 10.1093/nar/gkl640. View

Mottus R, Sobel R, Grigliatti T . Mutational analysis of a histone deacetylase in Drosophila melanogaster: missense mutations suppress gene silencing associated with position effect variegation. Genetics. 2000; 154(2):657-68. PMC: 1460943. DOI: 10.1093/genetics/154.2.657. View

Ding Z, Gillespie L, Paterno G . Human MI-ER1 alpha and beta function as transcriptional repressors by recruitment of histone deacetylase 1 to their conserved ELM2 domain. Mol Cell Biol. 2002; 23(1):250-8. PMC: 140656. DOI: 10.1128/MCB.23.1.250-258.2003. View

Lachner M, OSullivan R, Jenuwein T . An epigenetic road map for histone lysine methylation. J Cell Sci. 2003; 116(Pt 11):2117-24. DOI: 10.1242/jcs.00493. View

Zhang S, Xu L, Lee J, Xu T . Drosophila atrophin homolog functions as a transcriptional corepressor in multiple developmental processes. Cell. 2002; 108(1):45-56. DOI: 10.1016/s0092-8674(01)00630-4. View

Seum C, Bontron S, Reo E, Delattre M, Spierer P . Drosophila G9a is a nonessential gene. Genetics. 2007; 177(3):1955-7. PMC: 2147950. DOI: 10.1534/genetics.107.078220. View

Shi Y, Matson C, Lan F, Iwase S, Baba T, Shi Y . Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell. 2005; 19(6):857-64. DOI: 10.1016/j.molcel.2005.08.027. View

Rice J, Briggs S, Ueberheide B, Barber C, Shabanowitz J, Hunt D . Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell. 2003; 12(6):1591-8. DOI: 10.1016/s1097-2765(03)00479-9. View

10.

Mizutani A, Wang L, Rajan H, Vig P, Alaynick W, Thaler J . Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J. 2005; 24(18):3339-51. PMC: 1224676. DOI: 10.1038/sj.emboj.7600785. View

11.

Kubicek S, OSullivan R, August E, Hickey E, Zhang Q, Teodoro M . Reversal of H3K9me2 by a small-molecule inhibitor for the G9a histone methyltransferase. Mol Cell. 2007; 25(3):473-81. DOI: 10.1016/j.molcel.2007.01.017. View

12.

Paterno G, Li Y, Luchman H, Ryan P, Gillespie L . cDNA cloning of a novel, developmentally regulated immediate early gene activated by fibroblast growth factor and encoding a nuclear protein. J Biol Chem. 1997; 272(41):25591-5. DOI: 10.1074/jbc.272.41.25591. View

13.

Guenther M, Barak O, Lazar M . The SMRT and N-CoR corepressors are activating cofactors for histone deacetylase 3. Mol Cell Biol. 2001; 21(18):6091-101. PMC: 87326. DOI: 10.1128/MCB.21.18.6091-6101.2001. View

14.

Koide R, Ikeuchi T, Onodera O, Tanaka H, Igarashi S, Endo K . Unstable expansion of CAG repeat in hereditary dentatorubral-pallidoluysian atrophy (DRPLA). Nat Genet. 1994; 6(1):9-13. DOI: 10.1038/ng0194-9. View

15.

Nagafuchi S, Yanagisawa H, Ohsaki E, Shirayama T, Tadokoro K, Inoue T . Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA). Nat Genet. 1994; 8(2):177-82. DOI: 10.1038/ng1094-177. View

16.

Tong J, Hassig C, Schnitzler G, Kingston R, Schreiber S . Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature. 1998; 395(6705):917-21. DOI: 10.1038/27699. View

17.

Zhang Y, Leroy G, Seelig H, Lane W, Reinberg D . The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell. 1998; 95(2):279-89. DOI: 10.1016/s0092-8674(00)81758-4. View

18.

Tsai C, Kao H, Mitzutani A, Banayo E, Rajan H, McKeown M . Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors. Proc Natl Acad Sci U S A. 2004; 101(12):4047-52. PMC: 384693. DOI: 10.1073/pnas.0400615101. View

19.

Wood J, Nucifora Jr F, Duan K, Zhang C, Wang J, Kim Y . Atrophin-1, the dentato-rubral and pallido-luysian atrophy gene product, interacts with ETO/MTG8 in the nuclear matrix and represses transcription. J Cell Biol. 2000; 150(5):939-48. PMC: 2175251. DOI: 10.1083/jcb.150.5.939. View

20.

Mis J, Ner S, Grigliatti T . Identification of three histone methyltransferases in Drosophila: dG9a is a suppressor of PEV and is required for gene silencing. Mol Genet Genomics. 2006; 275(6):513-26. DOI: 10.1007/s00438-006-0116-x. View