Myocardial reprogramming by HMGN1 underlies heart defects in trisomy 21

Area of Science:

• Developmental Biology
• Genetics
• Cardiovascular Research

Background:

• Congenital heart defects (CHDs) are common, with aneuploidy, particularly trisomy 21 (Down syndrome), significantly increasing risk.
• Down syndrome is associated with a high incidence of CHDs, especially atrioventricular canal (AVC) defects, but causal genes remain unidentified.
• AVC development relies on unique myocardial cells, and the specific genetic drivers of Down syndrome-associated CHDs are unknown.

Purpose of the Study:

• To identify dosage-sensitive genes on chromosome 21 responsible for congenital heart defects in Down syndrome.
• To investigate the role of HMGN1 in the pathogenesis of Down syndrome-associated cardiac abnormalities.
• To establish a model for dissecting aneuploidy-associated diseases using isogenic systems.

Main Methods:

• Utilized human pluripotent stem cell and mouse models of Down syndrome.
• Performed single-cell transcriptomics to analyze cardiomyocyte states in trisomy 21.
• Conducted a CRISPR-activation single-cell RNA droplet sequencing (CROP-seq) screen of chromosome 21 genes.

Main Results:

• Trisomy 21 shifts human AVC cardiomyocytes towards a ventricular state.
• Upregulation of HMGN1 mimics this shift; reducing HMGN1 dosage in trisomic cells normalizes gene expression.
• Reduced Hmgn1 dosage in a mouse model rescued valvuloseptal defects, identifying HMGN1 as a key modulator.

Conclusions:

• HMGN1 is a dosage-sensitive regulator of AVC development and cardiac septation in Down syndrome.
• This study provides a paradigm for mapping causal genes in aneuploidy syndromes using isogenic systems.
• Findings highlight HMGN1's critical role in heart development and Down syndrome-associated CHDs.