Developmentally linked human DNA hypermethylation is associated with down-modulation, repression, and upregulation of transcription.
Developmentally linked human DNA hypermethylation is associated with down-modulation, repression, and upregulation of transcription.
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DOI：
10.1080/15592294.2018.1445900
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Ehrlich M
中科院分区：
文献类型：
--
作者：
Baribault C;Ehrlich KC;Ponnaluri VKC;Pradhan S;Lacey M;Ehrlich M
DNA甲基化可以影响组织特异性基因转录的方式，很难从集中于差异甲基化区域（DMRs）全基因组分析的研究中辨别出来。为了阐明分化相关DNA高甲基化和转录之间的各种关联，我们使用了来自38种人类细胞/组织类型的表观基因组和转录组谱，重点研究了与成肌细胞（Mb）中DMRs高甲基化相关的94个基因的这种关系。对于其中的19个基因，Mb（通常是少数异种细胞类型）中的启动子区域超甲基化与基因抑制有关，但重要的是，DNA超甲基化在许多其他抑制样本中不存在。在另外24个基因中，DNA超甲基化与隐增强子或超增强子重叠，并与下调但不沉默的基因表达相关。然而，令人惊讶的是，在非表达样本和高表达样本中都没有这种甲基化。这表明一些基因需要DMR高甲基化来帮助抑制隐藏增强子染色质，只有当它们被积极转录时。对于另外11个基因，我们发现基因间高甲基化DMRs与Mb中基因的阳性表达之间存在关联。与Mb相似的DNA高甲基化/转录相关性有时在不同的组织中很明显，如主动脉和大脑。我们的研究结果提示甲基化DNA可能与杜氏肌营养不良症、先天性心脏畸形和癌症有关。这种表观基因组分析表明，DNA甲基化不仅仅是基因表达变化的必然结果，相反，它通常是与发育相关的微调转录的活跃因子。
DNA methylation can affect tissue-specific gene transcription in ways that are difficult to discern from studies focused on genome-wide analyses of differentially methylated regions (DMRs). To elucidate the variety of associations between differentiation-related DNA hypermethylation and transcription, we used available epigenomic and transcriptomic profiles from 38 human cell/tissue types to focus on such relationships in 94 genes linked to hypermethylated DMRs in myoblasts (Mb). For 19 of the genes, promoter-region hypermethylation in Mb (and often a few heterologous cell types) was associated with gene repression but, importantly, DNA hypermethylation was absent in many other repressed samples. In another 24 genes, DNA hypermethylation overlapped cryptic enhancers or super-enhancers and correlated with down-modulated, but not silenced, gene expression. However, such methylation was absent, surprisingly, in both non-expressing samples and highly expressing samples. This suggests that some genes need DMR hypermethylation to help repress cryptic enhancer chromatin only when they are actively transcribed. For another 11 genes, we found an association between intergenic hypermethylated DMRs and positive expression of the gene in Mb. DNA hypermethylation/transcription correlations similar to those of Mb were evident sometimes in diverse tissues, such as aorta and brain. Our findings have implications for the possible involvement of methylated DNA in Duchenne's muscular dystrophy, congenital heart malformations, and cancer. This epigenomic analysis suggests that DNA methylation is not simply the inevitable consequence of changes in gene expression but, instead, is often an active agent for fine-tuning transcription in association with development.
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影响因子：
46.9
作者：
Ball, Madeleine P.;Li, Jin Billy;Gao, Yuan;Lee, Je-Hyuk;LeProust, Emily M.;Park, In-Hyun;Xie, Bin;Daley, George Q.;Church, George M.
通讯作者：
Church, George M.
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
12.3
作者：
Heyn H;Vidal E;Ferreira HJ;Vizoso M;Sayols S;Gomez A;Moran S;Boque-Sastre R;Guil S;Martinez-Cardus A;Lin CY;Royo R;Sanchez-Mut JV;Martinez R;Gut M;Torrents D;Orozco M;Gut I;Young RA;Esteller M
通讯作者：
Esteller M
影响因子：
16
作者：
Charlet J;Duymich CE;Lay FD;Mundbjerg K;Dalsgaard Sørensen K;Liang G;Jones PA
通讯作者：
Jones PA
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA