PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.
PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.
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DOI：
10.1161/circulationaha.121.056666
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发表时间：
2022-02-22
期刊：
影响因子：
37.8
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Wu T;Liang Z;Zhang Z;Liu C;Zhang L;Gu Y;Peterson KL;Evans SM;Fu XD;Chen J
左室致密化不全性心肌病（LVNC）是世纪前发现的一种以心肌小梁形成过多和室壁较薄为特征的心肌病。在此后的几十年中，许多研究表明LVNC主要影响左心室（LV），并且通常与LV扩张和功能障碍相关。然而，部分由于缺乏合适的小鼠模型，忠实地反映了患者的选择性LV脆弱性，潜在的机制LV扩张和功能障碍的敏感性LVNC仍然未知。遗传学研究表明，PRDM 16的缺失和突变导致LVNC，但以前的条件性Prdm 16敲除小鼠模型不能反映患者的LVNC表型，重要的是，PRDM 16缺陷导致LVNC的潜在分子机制仍不清楚。产生Prdm 16心肌细胞（CM）特异性敲除（Prdm 16 cKO）小鼠并分析心脏表型。进行RNA测序和ChIP测序以鉴定CM中PRDM 16的直接转录靶标。采用单细胞RNA测序结合空间转录组学来确定单细胞水平的CM身份。CM特异性消融Prdm 16在小鼠中引起LV特异性扩张和功能障碍，以及双心室致密化不全，这完全重现了患者的LVNC。机制上，PRDM 16作为致密心肌富集的转录因子，其在LV致密心肌中激活致密心肌基因而抑制小梁心肌基因。因此，Prdm 16 cKO LV致密心肌CM从其正常的转录组学身份转变为类似于小梁心肌CM和/或神经元的转录特征。PRDM 16的室特异性转录调节部分是由于其与LV富集的转录因子Tbx 5和Hand 1的合作。这些结果表明，破坏适当规格的紧凑CM可能在LVNC的发病机制中起着关键作用。他们还阐明了LV限制性转录程序控制LV室生长和成熟的潜在机制，为LV在LVNC心肌病亚组中的易感性提供了切实的解释。
Left ventricular noncompaction cardiomyopathy (LVNC) was discovered half a century ago as a cardiomyopathy with excessive trabeculation and a thin ventricular wall. In the decades since, numerous studies have demonstrated that LVNC primarily impacts left ventricles (LVs), and is often associated with LV dilation and dysfunction. However, owing in part to the lack of suitable mouse models that faithfully mirror the selective LV vulnerability in patients, mechanisms underlying susceptibility of LV to dilation and dysfunction in LVNC remain unknown. Genetic studies have revealed that deletions and mutations in PRDM16 cause LVNC, but previous conditional Prdm16 knockout mouse models do not mirror the LVNC phenotype in patients, and importantly, the underlying molecular mechanisms by which PRDM16 deficiency causes LVNC are still unclear. Prdm16 cardiomyocyte (CM)-specific knockout (Prdm16cKO) mice were generated and analyzed for cardiac phenotypes. RNA sequencing and ChIP sequencing were performed to identify direct transcriptional targets of PRDM16 in CMs. Single cell RNA sequencing in combination with Spatial Transcriptomics were employed to determine CM identity at single cell level. CM-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients. Mechanistically, PRDM16 functioned as a compact myocardium-enriched transcription factor, which activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium. Consequently, Prdm16cKO LV compact myocardial CMs shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial CMs and/or neurons. Chamber-specific transcriptional regulation by PRDM16 was in part due to its cooperation with LV-enriched transcription factors Tbx5 and Hand1. These results demonstrate that disruption of proper specification of compact CM may play a key role in the pathogenesis of LVNC. They also shed light on underlying mechanisms of LV-restricted transcriptional program governing LV chamber growth and maturation, providing a tangible explanation for the susceptibility of LV in a subset of LVNC cardiomyopathies.