Shi Wei, Wasson Lauren K, Dorr Kerry M, Robbe Zachary L, Wilczewski Caralynn M, Hepperla Austin J, Davis Ian J, Seidman Christine E, Seidman Jonathan G, Conlon Frank L
Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Development. 2024 Apr 15;151(8). doi: 10.1242/dev.202505. Epub 2024 May 3.
Regulation of chromatin states is essential for proper temporal and spatial gene expression. Chromatin states are modulated by remodeling complexes composed of components that have enzymatic activities. CHD4 is the catalytic core of the nucleosome remodeling and deacetylase (NuRD) complex, which represses gene transcription. However, it remains to be determined how CHD4, a ubiquitous enzyme that remodels chromatin structure, functions in cardiomyocytes to maintain heart development. In particular, whether other proteins besides the NuRD components interact with CHD4 in the heart is controversial. Using quantitative proteomics, we identified that CHD4 interacts with SMYD1, a striated muscle-restricted histone methyltransferase that is essential for cardiomyocyte differentiation and cardiac morphogenesis. Comprehensive transcriptomic and chromatin accessibility studies of Smyd1 and Chd4 null embryonic mouse hearts revealed that SMYD1 and CHD4 repress a group of common genes and pathways involved in glycolysis, response to hypoxia, and angiogenesis. Our study reveals a mechanism by which CHD4 functions during heart development, and a previously uncharacterized mechanism regarding how SMYD1 represses cardiac transcription in the developing heart.
染色质状态的调控对于基因在正确的时间和空间上表达至关重要。染色质状态由由具有酶活性的成分组成的重塑复合物调节。CHD4是核小体重塑和去乙酰化酶(NuRD)复合物的催化核心,该复合物可抑制基因转录。然而,作为一种重塑染色质结构的普遍存在的酶,CHD4如何在心肌细胞中发挥作用以维持心脏发育仍有待确定。特别是,除了NuRD成分之外,是否还有其他蛋白质在心脏中与CHD4相互作用仍存在争议。我们通过定量蛋白质组学鉴定出CHD4与SMYD1相互作用,SMYD1是一种横纹肌限制性组蛋白甲基转移酶,对心肌细胞分化和心脏形态发生至关重要。对Smyd1和Chd4基因敲除的胚胎小鼠心脏进行的全面转录组和染色质可及性研究表明,SMYD1和CHD4抑制了一组参与糖酵解、缺氧反应和血管生成的共同基因和信号通路。我们的研究揭示了CHD4在心脏发育过程中发挥作用的机制,以及一种关于SMYD1如何在发育中的心脏中抑制心脏转录的此前未被描述的机制。