加州大学Deepak Srivastava小组近日取得一项新成果。经过不懈努力，他们的研究显示，心肌重编程HMGN1是21三体心脏缺陷的基础。该研究于2025年10月22日发表于国际一流学术期刊《自然》杂志上。

通过研究人类多能干细胞和唐氏综合征的单主题模型，该研究团队发现21号染色体上编码的核小体结合表观遗传调节因子HMGN1是导致这些缺陷的关键因素。单细胞转录组学显示21三体将人类AVC心肌细胞转变为心室心肌细胞状态。CRISPR激活单细胞RNA液滴测序（CROP-seq）筛选心脏发育过程中表达的21号染色体基因显示，HMGN1上调模拟了这种转变，而三体细胞中一个HMGN1等位基因的缺失恢复了正常的基因表达。在21三体的小鼠模型中，通过减少Hmgn1剂量，AVC心肌细胞的类似转录转移得以恢复，从而挽救了瓣膜间隔缺损。这些发现确定HMGN1是唐氏综合征AVC发展和心脏间隔的剂量敏感调节剂。本研究为解剖非整倍体相关的发病机制主题等基因系统以绘制复杂遗传综合征的遗传基因图谱提供了一个范例。

据了解，先天性心脏缺陷（CHDs）是最常见的发育异常，影响约1%的活产婴儿。非整倍体约占冠心病的15%，其中21三体（也称为唐氏综合症）是最常见的形式。约50%的唐氏综合征患者会发生冠心病，其房室管（AVC）缺陷的富集程度约为1000倍，这种缺陷会破坏心房和心室之间的连接。AVC包含独特的心肌细胞，对瓣膜间隔发育至关重要；然而，21号染色体上导致唐氏综合征相关冠心病的剂量敏感基因的具体组合仍然未知。

附：英文原文

Title: Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21

Author: Ranade, Sanjeev S., Li, Feiya, Whalen, Sean, Pelonero, Angelo, Ye, Lin, Huang, Yu, Brand, Abigail, Nishino, Tomohiro, Mital, Rahul, Boileau, Ryan M., Koback, Frances, Padmanabhan, Arun, Yu, Victoria, Cimarosti, Bastien, Presas-Ramos, Diana, Merriman, Alexander F., Wallace, Langley Grace, Nguyen, Annie, Poulis, Nikolaos, Costa, Mauro W., Gifford, Casey A., Pollard, Katherine S., Srivastava, Deepak

Issue&Volume: 2025-10-22

Abstract: Congenital heart defects (CHDs) are the most common developmental abnormalities, affecting around 1% of live births1. Aneuploidy causes around 15% of CHDs, with trisomy 21 (also known as Down syndrome) being the most frequent form2. CHDs occur in around 50% of cases of Down syndrome, with an approximately 1,000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction between the atria and ventricles3,4. The AVC contains unique myocardial cells that are essential for valvuloseptal development; however, the specific combination of dosage-sensitive genes on chromosome 21 that are responsible for Down syndrome-associated CHDs have remained unknown. Here, using human pluripotent stem cell and mouse models of Down syndrome, we identify HMGN1, a nucleosome-binding epigenetic regulator encoded on chromosome 21, as a key contributor to these defects. Single-cell transcriptomics showed that trisomy 21 shifts human AVC cardiomyocytes towards a ventricular cardiomyocyte state. A CRISPR-activation single-cell RNA droplet sequencing (CROP-seq) screen of chromosome 21 genes expressed during heart development revealed that HMGN1 upregulation mimics this shift, whereas deletion of one HMGN1 allele in trisomic cells restored normal gene expression. In a mouse model of trisomy 21, a similar transcriptional shift of AVC cardiomyocytes was restored by a reduction in Hmgn1 dosage, leading to rescue of valvuloseptal defects. These findings identify HMGN1 as a dosage-sensitive modulator of AVC development and cardiac septation in Down syndrome. This study offers a paradigm for dissecting aneuploidy-associated pathogenesis using isogenic systems to map causal genes in complex genetic syndromes.

DOI: 10.1038/s41586-025-09593-9

Source: https://www.nature.com/articles/s41586-025-09593-9