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Lsh 介导的 RNA 聚合酶 II 在 HoxC6 和 HoxC8 处的停滞涉及 DNA 甲基化。

Lsh mediated RNA polymerase II stalling at HoxC6 and HoxC8 involves DNA methylation.

机构信息

Laboratory of Cancer Prevention, SAIC-Frederick, National Cancer Institute, Frederick, Maryland, United States of America.

出版信息

PLoS One. 2010 Feb 11;5(2):e9163. doi: 10.1371/journal.pone.0009163.

DOI:10.1371/journal.pone.0009163
PMID:20161795
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2820093/
Abstract

DNA cytosine methylation is an important epigenetic mechanism that is involved in transcriptional silencing of developmental genes. Several molecular pathways have been described that interfere with Pol II initiation, but at individual genes the molecular mechanism of repression remains uncertain. Here, we study the molecular mechanism of transcriptional regulation at Hox genes in dependence of the epigenetic regulator Lsh that controls CpG methylation at selected Hox genes. Wild type cells show a nucleosomal deprived region around the transcriptional start site at methylated Hox genes and mediate gene silencing via Pol II stalling. Hypomethylation in Lsh-/- cells is associated with efficient transcriptional elongation and splicing, in part mediated by the chromodomain protein Chd1. Dynamic modulation of DNA methylation in Lsh-/- and wild type cells demonstrates that catalytically active DNA methyltransferase activity is required for Pol II stalling. Taken together, the data suggests that DNA methylation can be compatible with Pol II binding at selected genes and Pol II stalling can act as alternate mechanism to explain transcriptional silencing associated with DNA methylation.

摘要

DNA 胞嘧啶甲基化是一种重要的表观遗传机制，参与发育基因的转录沉默。已经描述了几种干扰 Pol II 起始的分子途径，但在单个基因中，抑制的分子机制仍然不确定。在这里，我们研究了依赖于表观遗传调节剂 Lsh 的 Hox 基因转录调控的分子机制，Lsh 控制选定 Hox 基因的 CpG 甲基化。野生型细胞在甲基化 Hox 基因的转录起始位点周围显示出缺乏核小体的区域，并通过 Pol II 停滞介导基因沉默。Lsh-/-细胞中的低甲基化与有效的转录延伸和剪接有关，部分是由染色质域蛋白 Chd1 介导的。Lsh-/-和野生型细胞中 DNA 甲基化的动态调节表明，具有催化活性的 DNA 甲基转移酶活性是 Pol II 停滞所必需的。总之，这些数据表明 DNA 甲基化可以与选定基因的 Pol II 结合兼容，Pol II 停滞可以作为解释与 DNA 甲基化相关的转录沉默的替代机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1b6/2820093/30d1557d81b2/pone.0009163.g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1b6/2820093/30d1557d81b2/pone.0009163.g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1b6/2820093/1f8f47c1cfa3/pone.0009163.g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d1b6/2820093/30d1557d81b2/pone.0009163.g008.jpg

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