Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21 |

Congenital heart defects (CHD) are the most common developmental abnormalities affecting approximately 1% of live births.1. Aneuploidy accounts for approximately 15% of coronary heart disease, the most common form of which is trisomy 21 (also known as Down syndrome).2. CHD occurs in approximately 50% of Down syndrome cases, with an approximately 1000-fold increase in the incidence of relationship-disrupting atrioventricular canal (AVC) defects.connection between atria and ventricles3,4.AVC contains cells Cardiomyocytes are especially necessary for septal valve development;however, the specific combination of dose-sensitive genes on chromosome 21 responsible for Down syndrome-related CHD remains unknown.Here, using human and mouse pluripotent stem cell models of Down syndrome, we identify HMGN1, a nucleosome-associated epigenetic regulator encoded on chromosome 21, as a major effector cause of this defect.Single-cell transcriptomics shows that trisomy 21 converts human AVC cardiomyocytes to a ventricular cardiomyocyte state.CRISPR-enabled single-cell RNA-droplet sequencing (CROP-seq) screening of chromosome 21 genes expressed during cardiac development showed that downregulation of HMGN1 mimics this change, while deletion of one allele of HMGN1 in trisomic cells restored normal gene expression.In a trisomy 21 mouse model, a similar transcriptional shift of AVC cardiomyocytes was restored by Hmgn1 dosage reduction, leading to rescue of septal valve defects.These findings identify HMGN1 as a dose-sensitive modulator of AVC development and cardiac infection in Down syndrome.This study provides a model for dissecting aneuploidy-related pathogenesis using systemic copper to map causative genes in complex genetic syndromes.Studies using human pluripotent stem cells and mouse models of Down syndrome identify HMGN1 as a major contributor to congenital heart defects in individuals with Down syndrome.