H3K9me3-binding proteins are dispensable for SETDB1/H3K9me3-dependent retroviral silencing

Epigenetics & Chromatin

Matthew C Lorincz¹  Prim B Singh³  Dixie L Mager²  Misha Bilenky⁴  Jeremy P Brown³  Jörn Bullwinkel³  Preeti Goyal¹  Irina A Maksakova¹ 

[1] Department of Medical Genetics, Life Sciences Institute, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3;Terry Fox Laboratory, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L3;Division of Immunoepigenetics, Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany;Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC, V5Z 1L3, Canada

关键词: mouse embryonic stem cells;    transcriptional silencing;    retroviral repression;    H3K9me3;    Cbx5;    Cbx3;    Cbx1;    HP1;    heterochromatin protein 1;    ERV;    endogenous retrovirus;   

Others  :  823551
DOI  :  10.1186/1756-8935-4-12

 received in 2011-04-21, accepted in 2011-07-20,  发布年份 2011

【 摘 要 】

Background

Endogenous retroviruses (ERVs) are parasitic sequences whose derepression is associated with cancer and genomic instability. Many ERV families are silenced in mouse embryonic stem cells (mESCs) via SETDB1-deposited trimethylated lysine 9 of histone 3 (H3K9me3), but the mechanism of H3K9me3-dependent repression remains unknown. Multiple proteins, including members of the heterochromatin protein 1 (HP1) family, bind H3K9me2/3 and are involved in transcriptional silencing in model organisms. In this work, we address the role of such H3K9me2/3 "readers" in the silencing of ERVs in mESCs.

Results

We demonstrate that despite the reported function of HP1 proteins in H3K9me-dependent gene repression and the critical role of H3K9me3 in transcriptional silencing of class I and class II ERVs, the depletion of HP1α, HP1β and HP1γ, alone or in combination, is not sufficient for derepression of these elements in mESCs. While loss of HP1α or HP1β leads to modest defects in DNA methylation of ERVs or spreading of H4K20me3 into flanking genomic sequence, respectively, neither protein affects H3K9me3 or H4K20me3 in ERV bodies. Furthermore, using novel ERV reporter constructs targeted to a specific genomic site, we demonstrate that, relative to Setdb1, knockdown of the remaining known H3K9me3 readers expressed in mESCs, including Cdyl, Cdyl2, Cbx2, Cbx7, Mpp8, Uhrf1 and Jarid1a-c, leads to only modest proviral reactivation.

Conclusion

Taken together, these results reveal that each of the known H3K9me3-binding proteins is dispensable for SETDB1-mediated ERV silencing. We speculate that H3K9me3 might maintain ERVs in a silent state in mESCs by directly inhibiting deposition of active covalent histone marks.

【 授权许可】

   
2011 Maksakova et al; licensee BioMed Central Ltd.

【 图 表 】

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