Delineating chromatin accessibility re-patterning at single cell level during early stage of direct cardiac reprogramming.
Delineating chromatin accessibility re-patterning at single cell level during early stage of direct cardiac reprogramming.
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DOI：
10.1016/j.yjmcc.2021.09.002
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发表时间：
2022-01
影响因子：
5
通讯作者：
Qian L
中科院分区：
文献类型：
--
作者：
Wang H;Yang Y;Qian Y;Liu J;Qian L
通过强制表达心脏转录因子，如Mef 2c，Gata 4和Tbx 5（MGT），将心脏成纤维细胞直接转化为诱导心肌细胞（iCM），为再生医学带来了巨大的希望。心脏重编程的过程由转录组重构事件的波组成。然而，这种转录组重构是如何由上游染色质景观改变驱动的仍然不清楚。在这项研究中，我们对早在第3天已知的表观遗传变化的早期重编程iCM进行了单细胞ATAC-seq（使用测序进行的转座酶可降解染色质测定）。这种方法揭示了在心脏重编程过程中参与染色质可及性早期转移的转录因子（TF）网络。结合我们的分析与功能测定，我们确定Smad 3是心脏重编程中的双峰TF，重编程启动的屏障和重编程中间阶段的促进剂。此外，scATAC-seq与scRNA-seq数据的综合分析导致鉴定对iCM转化重要的活性TF。最后，我们发现了心脏基因顺式调控相互作用沿着重编程轨迹的全局重新布线。总的来说，我们的scATAC-seq研究和scRNA-seq数据的整合分析为理解表观基因组异质性及其在心脏重编程早期阶段与转录变化相关的改变提供了宝贵的资源。
Direct conversion of cardiac fibroblast into induced cardiomyocytes (iCMs) by forced expression of cardiac transcription factors, such as Mef2c, Gata4, and Tbx5 (MGT), holds great promise for regenerative medicine. The process of cardiac reprogramming consists of waves of transcriptome remodelling events. However, how this transcriptome remodelling is driven by the upstream chromatin landscape alteration is still unclear. In this study, we performed single-cell ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing) on early reprogramming iCMs given the known epigenetic changes as early as day 3. This approach unveiled networks of transcription factors (TFs) involved in the early shift of chromatin accessibility during cardiac reprogramming. Combining our analysis with functional assays, we identified Smad3 to be a bimodal TF in cardiac reprogramming, a barrier in the initiation of reprogramming and a facilitator during the intermediate stage of reprogramming. Moreover, integrative analysis of scATAC-seq with scRNA-seq data led to the identification of active TFs important for iCM conversion. Finally, we discovered a global rewiring of cis-regulatory interactions of cardiac genes along the reprogramming trajectory. Collectively, our scATAC-seq study and the integrative analysis with scRNA-seq data provided valuable resources to understand the epigenomic heterogeneity and its alteration in relation to transcription changes during early stage of cardiac reprogramming.
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影响因子：
64.8
作者：
Qian, Li;Huang, Yu;Srivastava, Deepak
通讯作者：
Srivastava, Deepak
影响因子：
1.2
作者：
Liu Z;Chen O;Zheng M;Wang L;Zhou Y;Yin C;Liu J;Qian L
通讯作者：
Qian L
通过对心脏转录因子的非肌细胞进行重编程通过重编程。
影响因子：
64.8
作者：
Song, Kunhua;Nam, Young-Jae;Luo, Xiang;Qi, Xiaoxia;Tan, Wei;Huang, Guo N.;Acharya, Asha;Smith, Christopher L.;Tallquist, Michelle D.;Neilson, Eric G.;Hill, Joseph A.;Bassel-Duby, Rhonda;Olson, Eric N.
通讯作者：
Olson, Eric N.
影响因子：
64.8
作者：
Laflamme, Michael A.;Murry, Charles E.
通讯作者：
Murry, Charles E.
影响因子：
14.9
作者：
Franceschini A;Szklarczyk D;Frankild S;Kuhn M;Simonovic M;Roth A;Lin J;Minguez P;Bork P;von Mering C;Jensen LJ
通讯作者：
Jensen LJ