DNMT3B Functions: Novel Insights From Human Disease.
DNMT3B Functions: Novel Insights From Human Disease.
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DOI：
10.3389/fcell.2018.00140
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发表时间：
2018
影响因子：
5.5
通讯作者：
Matarazzo MR
中科院分区：
文献类型：
--
作者：
Gagliardi M;Strazzullo M;Matarazzo MR
DNA甲基化在基因表达调控和染色质结构中发挥着重要作用。它的正确建立和维护对于哺乳动物的发育和细胞分化至关重要。 DNMT3B 是在胚胎发育早期（包括植入）期间表达和活跃的主要从头 DNA 甲基转移酶。除了众所周知的甲基化着丝粒、着丝粒周围和亚端粒重复的作用外，最近的观察表明 DNMT3B 还充当活性基因基因内区域甲基化的主要酶。尽管进行了大量研究，但关于这些从头 CpG 甲基化的特定模式是如何在哺乳动物细胞中建立的，以及控制 DNMT3B 招募和活性的规则，仍然有很多未知之处。最新证据表明 DNMT3B 招募受到多种机制的调节，包括染色质修饰、转录水平、非编码 RNA 和 DNA 结合因子的存在。 DNA甲基化异常是涉及染色体和基因组不稳定的人类疾病的常见标志，例如遗传性疾病和癌症。常染色体隐性遗传性免疫缺陷、着丝粒不稳定和面部异常综合征 I 型 (ICF-1) 与 DNMT3B 基因的低等位性突变有关，而其表达改变与肿瘤的发展相关。在这两种情况下，这意味着异常的 DNA 低甲基化和高甲基化模式会影响基因表达和基因组结构，从而导致病理状态。我们将概述最新的研究，旨在破译 DNMT3B 异常与这些病理的发生和进展相关的分子机制。
DNA methylation plays important roles in gene expression regulation and chromatin structure. Its proper establishment and maintenance are essential for mammalian development and cellular differentiation. DNMT3B is the major de novo DNA methyltransferase expressed and active during the early stage of embryonic development, including implantation. In addition to its well-known role to methylate centromeric, pericentromeric, and subtelomeric repeats, recent observations suggest that DNMT3B acts as the main enzyme methylating intragenic regions of active genes. Although largely studied, much remains unknown regarding how these specific patterns of de novo CpG methylation are established in mammalian cells, and which are the rules governing DNMT3B recruitment and activity. Latest evidence indicates that DNMT3B recruitment is regulated by numerous mechanisms including chromatin modifications, transcription levels, non-coding RNAs, and the presence of DNA-binding factors. DNA methylation abnormalities are a common mark of human diseases involving chromosomal and genomic instabilities, such as inherited disease and cancer. The autosomal recessive Immunodeficiency, Centromeric instability and Facial anomalies syndrome, type I (ICF-1), is associated to hypomorphic mutations in DNMT3B gene, while its altered expression has been correlated with the development of tumors. In both cases, this implies that abnormal DNA hypomethylation and hypermethylation patterns affect gene expression and genomic architecture contributing to the pathological states. We will provide an overview of the most recent research aimed at deciphering the molecular mechanisms by which DNMT3B abnormalities are associated with the onset and progression of these pathologies.