Department of Surgery, Weill Cornell Medical College, New York, NY 10065, USA.
Department of Physiology and Biophysics, Englander Institute for Precision Medicine, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10065, USA.
Cell Rep. 2019 Jan 15;26(3):720-732.e4. doi: 10.1016/j.celrep.2018.12.076.
Ten-eleven translocation (Tet) enzymes (Tet1/2/3) mediate 5-methylcytosine (5mC) hydroxylation, which can facilitate DNA demethylation and thereby impact gene expression. Studied mostly for how mutant isoforms impact cancer, the normal roles for Tet enzymes during organogenesis are largely unknown. By analyzing compound mutant zebrafish, we discovered a requirement for Tet2/3 activity in the embryonic heart for recruitment of epicardial progenitors, associated with development of the atrial-ventricular canal (AVC). Through a combination of methylation, hydroxymethylation, and transcript profiling, the genes encoding the activin A subunit Inhbaa (in endocardium) and Sox9b (in myocardium) were implicated as demethylation targets of Tet2/3 and critical for organization of AVC-localized extracellular matrix (ECM), facilitating migration of epicardial progenitors onto the developing heart tube. This study elucidates essential DNA demethylation modifications that govern gene expression changes during cardiac development with striking temporal and lineage specificities, highlighting complex interactions in multiple cell populations during development of the vertebrate heart.
十十一号转位酶（Tet）（Tet1/2/3）介导 5-甲基胞嘧啶（5mC）羟化，可促进 DNA 去甲基化，从而影响基因表达。虽然研究主要集中在突变同工酶如何影响癌症，但 Tet 酶在器官发生过程中的正常作用在很大程度上尚不清楚。通过分析复合突变斑马鱼，我们发现 Tet2/3 活性在胚胎心脏中对于招募心外膜祖细胞是必需的，这与心房-心室管（AVC）的发育有关。通过甲基化、羟甲基化和转录谱分析，编码激活素 A 亚基 Inhbaa（在心内膜）和 Sox9b（在心肌）的基因被认为是 Tet2/3 的去甲基化靶标，对于 AVC 局部细胞外基质（ECM）的组织至关重要，促进心外膜祖细胞迁移到正在发育的心脏管上。这项研究阐明了在心脏发育过程中控制基因表达变化的必需 DNA 去甲基化修饰，具有显著的时间和谱系特异性，突出了在脊椎动物心脏发育过程中多个细胞群之间的复杂相互作用。
