Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin
Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin
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DOI：
10.1074/jbc.m104661200
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发表时间：
2001-08-24
影响因子：
4.8
通讯作者：
Baylin, SB
中科院分区：
文献类型：
--
作者：
Bachman, KE;Rountree, MR;Baylin, SB
我们证明，最近确定的DNA甲基转移酶，Dnmt 3a和Dnmt 3b，像DNMT 1，抑制转录甲基化独立的方式。Dnmt 3a和Dnmt 3b主要通过与ATRX蛋白共享但不存在于DNMT 1中的植物同源结构域样基序抑制转录。与DNMT 1不同，DNMT 1在鼠胚胎成纤维细胞的S期定位于复制灶，Dnmt 3a在整个细胞周期中与异染色质蛋白Ia（HP 1 α）和甲基-CpG结合蛋白共定位于晚期复制的近着丝粒异染色质。与Dnmt 3a相反，Dnmt 3b在胚胎成纤维细胞的细胞核中在所有细胞周期阶段保持弥漫。然而，在小鼠胚胎干细胞中，Dnmt 3a和Dnmt 3b共定位于这些着丝粒周围异染色质区域。这一发现对于DNMT 3B突变在发育综合征ICF（免疫缺陷、着丝粒异染色质不稳定和面部异常）中发现的事实是重要的，所述发育综合征ICF涉及从着丝粒周围区域的甲基化的广泛丢失。Dnmt 3a和Dnmt 3b的定位在Dnmt 1无效的胚胎干细胞中不受影响，这些胚胎干细胞在近着丝粒主要卫星重复序列处失去了大部分甲基化，这表明这些酶不依赖于预先存在的甲基化。然后，DNMT 1被定位以在细胞复制时重建转录抑制性染色质，而Dnmt 3a和Dnmt 3b可能有助于在S期晚期建立这种染色质，并以发育和/或细胞类型的方式在整个细胞周期中维持这种抑制性异染色质。
We demonstrate that the recently identified DNA methyltransferases, Dnmt3a and Dnmt3b, like DNMT1, repress transcription in a methylation-independent manner. Dnmt3a and Dnmt3b repress transcription primarily through a plant homeodomain-like motif that is shared with the ATRX protein but is not present in DNMT1. Unlike DNMT1, which localizes to replication foci during S-phase in murine embryonic fibroblasts, Dnmt3a co-localizes with heterochromatin protein I a (HP1 alpha) and methyl-CpG binding proteins throughout the cell cycle to late-replicating pericentromeric heterochromatin. In contrast to Dnmt3a, Dnmt3b remained diffuse in the nucleus of embryonic fibroblasts at all cell cycle stages. However, Dnmt3a and Dnmt3b co-localize to these pericentromeric heterochromatin regions in murine embryonic stem cells. This finding is important to the fact that mutations in DNMT3B are found in the developmental syndrome, ICF (immunodeficiency, centromeric heterochromatin instability, and facial anomalies), which involves extensive loss of methylation from pericentromeric regions. The localization of Dnmt3a and Dnmt3b was unaffected in Dnmt1 null embryonic stem cells, which lose the majority of methylation at pericentromeric major satellite repeats, suggesting that these enzymes are not dependent upon preexisting methylation for their targeting. DNMT1 is then positioned to reestablish transcriptionally repressive chromatin as cells replicate, while Dnmt3a and Dnmt3b may help to establish such chromatin in late S-phase and maintain this repressive heterochromatin throughout the cell cycle in a developmentally and/or cell type manner.