Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Genetics Bioinformatics Service Center, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell Stem Cell. 2018 Mar 1;22(3):428-444.e5. doi: 10.1016/j.stem.2018.02.005.
Cardiac development requires coordinated and large-scale rearrangements of the epigenome. The roles and precise mechanisms through which specific epigenetic modifying enzymes control cardiac lineage specification, however, remain unclear. Here we show that the H3K4 methyltransferase SETD7 controls cardiac differentiation by reading H3K36 marks independently of its enzymatic activity. Through chromatin immunoprecipitation sequencing (ChIP-seq), we found that SETD7 targets distinct sets of genes to drive their stage-specific expression during cardiomyocyte differentiation. SETD7 associates with different co-factors at these stages, including SWI/SNF chromatin-remodeling factors during mesodermal formation and the transcription factor NKX2.5 in cardiac progenitors to drive their differentiation. Further analyses revealed that SETD7 binds methylated H3K36 in the bodies of its target genes to facilitate RNA polymerase II (Pol II)-dependent transcription. Moreover, abnormal SETD7 expression impairs functional attributes of terminally differentiated cardiomyocytes. Together, these results reveal how SETD7 acts at sequential steps in cardiac lineage commitment, and they provide insights into crosstalk between dynamic epigenetic marks and chromatin-modifying enzymes.
心脏发育需要表观基因组的协调和大规模重排。然而，特定的表观遗传修饰酶控制心脏谱系特化的确切机制和作用仍不清楚。在这里，我们表明，H3K4 甲基转移酶 SETD7 通过独立于其酶活性读取 H3K36 标记来控制心脏分化。通过染色质免疫沉淀测序 (ChIP-seq)，我们发现 SETD7 靶向不同的基因集，以在心肌细胞分化过程中驱动其阶段特异性表达。SETD7 在这些阶段与不同的共因子结合，包括中胚层形成期间的 SWI/SNF 染色质重塑因子和心脏祖细胞中的转录因子 NKX2.5，以驱动它们的分化。进一步的分析表明，SETD7 结合其靶基因的 H3K36 甲基化，以促进 RNA 聚合酶 II (Pol II) 依赖性转录。此外，异常的 SETD7 表达会损害终末分化的心肌细胞的功能属性。总之，这些结果揭示了 SETD7 如何在心脏谱系特化的连续步骤中发挥作用，并为动态表观遗传标记和染色质修饰酶之间的串扰提供了见解。
