AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans
AS1DHRS4, a head-to-head natural antisense transcript, silences the DHRS4 gene cluster in cis and trans
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AS1DHRS4，一种头对头的天然反义转录物，以顺式和反式沉默 DHRS4 基因簇
DOI：
10.1073/pnas.1116597109
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发表时间：
2012-08-28
影响因子：
11.1
通讯作者：
Huang, Dongyang
中科院分区：
文献类型：
--
作者：
Li, Qi;Su, Zhongjing;Huang, Dongyang
人类基因组，像其他哺乳动物基因组一样，编码许多天然反义转录物（NAT），这些转录物根据其正义转录物被分为头对头、尾对尾或完全重叠的类别。NAT介导的有义转录表观遗传沉默的证据仍然很少。DHRS4基因编码一种代谢酶，并与其两个直接下游同源基因DHRS4L2和DHRS4L1形成一个基因簇，这两个同源基因是通过基因复制产生的。我们鉴定了DHRS4的头对头NAT，命名为AS1DHRS4，其显著调节DHRS4基因簇中这三个基因的表达。通过与持续的有义转录本配对，AS 1 DHRS 4不仅介导DHRS 4基因顺式组蛋白H3的脱乙酰化和H3 K4的脱甲基化，而且还与表观遗传修饰剂H3 K9和H3 K27特异性组蛋白甲基转移酶G9 a和EZH 2反式物理相互作用。靶向下游DHRS4L2和DHRS4L1基因的启动子以诱导局部抑制性H3K9me2和H3K27me3组蛋白修饰。此外，AS1DHRS4通过募集DNA甲基转移酶诱导DHRS4L2启动子区的DNA甲基化。这项研究表明，AS1DHRS4，作为一个长的非编码RNA，同时控制的DHRS4基因簇内的每个基因的染色质状态的歧视性的方式。这一发现提供了一个例子，转录控制的多个和高度同源的基因在一个紧密的基因簇，并可能有助于解释的作用，反义RNA的调节重复基因的基因组进化的结果。
The human genome, like other mammalian genomes, encodes numerous natural antisense transcripts (NATs) that have been classified into head-to-head, tail-to-tail, or fully overlapped categories in reference to their sense transcripts. Evidence for NAT-mediated epigenetic silencing of sense transcription remains scanty. The DHRS4 gene encodes a metabolic enzyme and forms a gene cluster with its two immediately downstream homologous genes, DHRS4L2 and DHRS4L1, generated by gene duplication. We identified a head-to-head NAT of DHRS4, designated AS1DHRS4, which markedly regulates the expression of these three genes in the DHRS4 gene cluster. By pairing with ongoing sense transcripts, AS1DHRS4 not only mediates deacetylation of histone H3 and demethylation of H3K4 in cis for the DHRS4 gene, but also interacts physically in trans with the epigenetic modifiers H3K9- and H3K27-specific histone methyltransferases G9a and EZH2, targeting the promoters of the downstream DHRS4L2 and DHRS4L1 genes to induce local repressive H3K9me2 and H3K27me3 histone modifications. Furthermore, AS1DHRS4 induces DNA methylation in the promoter regions of DHRS4L2 by recruiting DNA methyltransferases. This study demonstrates that AS1DHRS4, as a long noncoding RNA, simultaneously controls the chromatin state of each gene within the DHRS4 gene cluster in a discriminative manner. This finding provides an example of transcriptional control over the multiple and highly homologous genes in a tight gene cluster, and may help explain the role of antisense RNAs in the regulation of duplicated genes as the result of genomic evolution.