Retrovirus silencing, variegation, extinction, and memory are controlled by a dynamic interplay of multiple epigenetic modifications

被引:95
作者
Yao, SY
Sukonnik, T
Kean, T
Bharadwaj, RR
Pasceri, P
Ellis, J
机构
[1] Hosp Sick Children, Dev Biol Program, Toronto, ON M5G 1X8, Canada
[2] Univ Toronto, Dept Mol & Med Genet, Toronto, ON, Canada
基金
加拿大健康研究院;
关键词
chromatin; DNA methylation; gene silencing; retrovirus; stem cells;
D O I
10.1016/j.ymthe.2004.04.007
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Retrovirus silencing in stem cells produces silent or variegated provirus. Additional memory and extinction mechanisms act during differentiation. Here we show that retrovirus is silent or variegated in mouse embryonic stem (ES) cells that are de novo methyltransferase (dnmt3a and dnmt3b) null. Memory is maintained during differentiation, and extinction occurs on variegated retrovirus, indicating that DNA methylation is dispensable for all forms of retrovirus silencing. Silent and variegated provirus are marked by hypoacetylated histone H3 and bound HI. In wildtype ES cells, silent and variegated proviruses are methylated and bound by hypoacetylated H3, MeCP2, and less HI. Silencing, variegation, and extinction are partially reactivated by 5-AzaC in this context. Lentivirus vectors are also silent or variegated, marked by silent chromatin, and exhibit memory and extinction. We conclude that the universal epigenetic mark of retrovirus silencing is silent chromatin established via the dynamic interplay of multiple epigenetic modifications that include but do not require DNA methylation. A molecular mechanism of competitive H1 and MeCP2 binding may account for this epigenetic interplay, and a model for variegation is discussed.
引用
收藏
页码:27 / 36
页数:10
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