Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome
Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome
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DOI：
10.3389/fgene.2015.00339
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发表时间：
2015-12-01
影响因子：
3.7
通讯作者：
Bierne, Helene
中科院分区：
文献类型：
--
作者：
Libertin, Emanuele;Lebreton, Alice;Bierne, Helene
BAH结构域蛋白1 （BAHD1）参与人类细胞异染色质形成和基因抑制。BAHD1也定位于失活的X染色体（Xi），但这种靶向的功能意义尚不清楚。到目前为止，对该蛋白的研究受到其内源性丰度较低的阻碍，其在表观遗传调控中的作用仍未得到充分的探索。在这项工作中，我们使用全基因组亚硫酸盐测序（BS-seq）来比较表达低水平BAHD1 （HEK-CT）的HEK293细胞与稳定过表达BAHD1 （HEK-BAHD1）的等基因细胞的DNA甲基化谱。研究表明，增加BAHD1水平可诱导常染色体上的DNA重新甲基化和X染色体（chrX）上的显著低甲基化。我们发现，与HEK-CT细胞相比，HEK-BAHD1中有91358个区域具有不同的甲基化模式（称为“BAHD1-DMRs”），其中83850个位于常染色体上，7508个位于X染色体（chrX）上。常染色体BAHD1-DMRs主要高甲基化，位于卫星区、散布重复区和基因间区。相比之下，chrX上的BAHD1-DMRs主要是低甲基化，定位于基因体和增强子。我们进一步发现BAHD1-DMRs通过聚集在大的染色体结构域内显示出更高阶的组织。这些“bahd1相关的差异甲基化结构域”（BADs）中有一半与层相关结构域（LADs）重叠。基于这些结果，我们提出bahd1介导的异染色质形成与DNA甲基化有关，并可能在基因组的空间结构中发挥作用。
BAH domain-containing protein 1 (BAHD1) is involved in heterochromatin formation and gene repression in human cells. BAHD1 also localizes to the inactive X chromosome (Xi), but the functional significance of this targeting is unknown. So far, research on this protein has been hampered by its low endogenous abundance and its role in epigenetic regulation remains poorly explored. In this work, we used whole-genome bisulfite sequencing (BS-seq) to compare the DNA methylation profile of HEK293 cells expressing low levels of BAHD1 (HEK-CT) to that of isogenic cells stably overexpressing BAHD1 (HEK-BAHD1). We show that increasing BAHD1 levels induces de novo DNA methylation on autosomes and a marked hypomethylation on the X chromosome (chrX). We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed "BAHD1-DMRs"), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX). Autosomal BAHD1-DMRs were predominantly hypermethylated and located to satellites, interspersed repeats, and intergenic regions. In contrast, BAHD1-DMRs on chrX were mainly hypomethylated and located to gene bodies and enhancers. We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains. Half of these "BAHD1-Associated differentially methylated Domains" (BADs) overlapped with lamina-associated domains (LADs). Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome.