ICF-specific DNMT3B dysfunction interferes with intragenic regulation of mRNA transcription and alternative splicing.
ICF-specific DNMT3B dysfunction interferes with intragenic regulation of mRNA transcription and alternative splicing.
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DOI：
10.1093/nar/gkx163
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发表时间：
2017-06-02
影响因子：
14.9
通讯作者：
Matarazzo MR
中科院分区：
文献类型：
--
作者：
Gatto S;Gagliardi M;Franzese M;Leppert S;Papa M;Cammisa M;Grillo G;Velasco G;Francastel C;Toubiana S;D'Esposito M;Angelini C;Matarazzo MR
DNA甲基转移酶DNMT 3B的亚型突变导致大多数罕见疾病免疫缺陷、着丝粒不稳定和面部异常综合征病例（ICF 1）。通过未指明的机制，muplant-DNMT 3B干扰淋巴特异性途径，导致免疫应答缺陷。有趣的是，最近的研究结果报告说，DNMT 3B形状高度转录基因的基因内CpG甲基化。然而，DNMT 3B依赖的表观遗传网络如何调节转录以及ICF 1特异性突变是否会损害这一过程仍然未知。我们在患者来源的B细胞系中进行了转录组学和表观基因组学研究，以研究DNMT 3B功能障碍的基因组规模效应。我们强调，改变基因内CpG甲基化损害转录调控的多个方面，如选择性TSS使用，反义转录和外显子剪接。这些缺陷优先与基因内H3 K4 me 3的变化相关，并且在较小程度上与H3 K27 me 3和H3 K36 me 3的变化相关。此外，我们强调了一种新的DNMT 3B活性，通过与RNA分子相互作用，调节有义-反义对的自我调节回路和选择性剪接过程中的外显子跳跃。引人注目的是，改变的转录影响疾病相关基因，例如记忆B细胞标志物CD 27和PTPRC基因，为我们提供了对ICF 1综合征发病机制的生物学见解。我们的基因组规模的方法揭示了DNMT 3B和DNA甲基化在基因表达调控中的基因内功能的机制仍然知之甚少。
Hypomorphic mutations in DNA-methyltransferase DNMT3B cause majority of the rare disorder Immunodeficiency, Centromere instability and Facial anomalies syndrome cases (ICF1). By unspecified mechanisms, mutant-DNMT3B interferes with lymphoid-specific pathways resulting in immune response defects. Interestingly, recent findings report that DNMT3B shapes intragenic CpG-methylation of highly-transcribed genes. However, how the DNMT3B-dependent epigenetic network modulates transcription and whether ICF1-specific mutations impair this process remains unknown. We performed a transcriptomic and epigenomic study in patient-derived B-cell lines to investigate the genome-scale effects of DNMT3B dysfunction. We highlighted that altered intragenic CpG-methylation impairs multiple aspects of transcriptional regulation, like alternative TSS usage, antisense transcription and exon splicing. These defects preferentially associate with changes of intragenic H3K4me3 and at lesser extent of H3K27me3 and H3K36me3. In addition, we highlighted a novel DNMT3B activity in modulating the self-regulatory circuit of sense-antisense pairs and the exon skipping during alternative splicing, through interacting with RNA molecules. Strikingly, altered transcription affects disease relevant genes, as for instance the memory-B cell marker CD27 and PTPRC genes, providing us with biological insights into the ICF1-syndrome pathogenesis. Our genome-scale approach sheds light on the mechanisms still poorly understood of the intragenic function of DNMT3B and DNA methylation in gene expression regulation.