Early adaptive chromatin remodeling events precede pathologic phenotypes and are reinforced in the failing heart.
Early adaptive chromatin remodeling events precede pathologic phenotypes and are reinforced in the failing heart.
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DOI：
10.1016/j.yjmcc.2021.07.002
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发表时间：
2021-11
影响因子：
5
通讯作者：
Rosa-Garrido, Manuel
中科院分区：
文献类型：
--
作者：
Chapski, Douglas J.;Cabaj, Maximilian;Morselli, Marco;Mason, Rosibel J.;Soehalim, Elizabeth;Ren, Shuxun;Pellegrini, Matteo;Wang, Yibin;Vondriska, Thomas M.;Rosa-Garrido, Manuel
人们对支撑病理转录的染色质结构变化的时间性质知之甚少。我们测量了染色质可及性和 DNA 甲基化，以研究染色质重塑在心脏肥大和衰竭的不同阶段的贡献。在横主动脉缩窄 (TAC) 或染色质结构蛋白 CTCF 耗尽后的心肌细胞中进行 ATAC-seq 和简化代表性亚硫酸氢盐测序。对压力超负荷的早期补偿显示染色质可及性和 DNA 甲基化的变化优先定位于基因间和内含子区域。在后期（TAC 后 3 周）增强子和启动子中观察到的大多数甲基化和可及性变化是在心力衰竭出现之前的较早时间点（TAC 后 3 天）建立的。增强子与基于染色质构象捕获数据的基因配对：虽然增强子可及性通常与基因表达的变化相关，但仅此特征或DNA甲基化就足以预测所有增强子相互作用基因的转录。这些区域转录因子和活性组蛋白标记的富集表明增强子活性与其他表观遗传因子协调来决定基因转录。为了支持这一假设，ChIP-qPCR 证明，GATA4 和 NKX2.5 在 Itga9 和 Nppa 处的增强子和启动子占有率分别增加，同时这些基因在患病心脏中的转录增加。最后，我们证明可及性和 DNA 甲基化是 A/B 区室化范围内染色质结构的不完美预测因子，相反，可及性、DNA 甲基化、转录因子和其他组蛋白标记在这些域内发挥作用来确定基因表达。这些研究证实，病理刺激后早期代偿期间的染色质重组一直维持到心力衰竭的后期失代偿阶段。这些发现揭示了局部染色质特征如何在全局基因组结构背景下控制基因表达的规则，并识别用于疾病治疗靶向的染色质重塑事件。
The temporal nature of chromatin structural changes underpinning pathologic transcription are poorly understood. We measured chromatin accessibility and DNA methylation to study the contribution of chromatin remodeling at different stages of cardiac hypertrophy and failure. ATAC-seq and reduced representation bisulfite sequencing were performed in cardiac myocytes after transverse aortic constriction (TAC) or depletion of the chromatin structural protein CTCF. Early compensation to pressure overload showed changes in chromatin accessibility and DNA methylation preferentially localized to intergenic and intronic regions. Most methylation and accessibility changes observed in enhancers and promoters at the late phase (3 weeks after TAC) were established at an earlier time point (3 days after TAC), before heart failure manifests. Enhancers were paired with genes based on chromatin conformation capture data: while enhancer accessibility generally correlated with changes in gene expression, this feature, nor DNA methylation, was alone sufficient to predict transcription of all enhancer interacting genes. Enrichment of transcription factors and active histone marks at these regions suggests that enhancer activity coordinates with other epigenetic factors to determine gene transcription. In support of this hypothesis, ChIP-qPCR demonstrated increased enhancer and promoter occupancy of GATA4 and NKX2.5 at Itga9 and Nppa, respectively, concomitant with increased transcription of these genes in the diseased heart. Lastly, we demonstrate that accessibility and DNA methylation are imperfect predictors of chromatin structure at the scale of A/B compartmentalization—rather, accessibility, DNA methylation, transcription factors and other histone marks work within these domains to determine gene expression. These studies establish that chromatin reorganization during early compensation after pathologic stimuli is maintained into the later decompensatory phases of heart failure. The findings reveal the rules for how local chromatin features govern gene expression in the context of global genomic structure and identify chromatin remodeling events for therapeutic targeting in disease.
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不同的表观遗传学计划调节体内人心脏中心肌细胞的发育和疾病。
影响因子：
16.6
作者：
Gilsbach R;Schwaderer M;Preissl S;Grüning BA;Kranzhöfer D;Schneider P;Nührenberg TG;Mulero-Navarro S;Weichenhan D;Braun C;Dreßen M;Jacobs AR;Lahm H;Doenst T;Backofen R;Krane M;Gelb BD;Hein L
通讯作者：
Hein L
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
20.1
作者：
Gillette TG;Hill JA
通讯作者：
Hill JA
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
6.1
作者：
Jalil, MA;Horiuchi, M;Saheki, T
通讯作者：
Saheki, T