HYDIN loss-of-function inhibits GATA4 expression and enhances atrial septal defect risk

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Genetics

Background:

• Congenital heart diseases (CHDs) arise from mutations in cardiac structural genes.
• Axonemal Central Pair Apparatus Protein (HYDIN), a ciliary protein, is linked to congenital cardiomyopathy, but its role in CHDs is unexplored.
• This study investigates HYDIN's function in heart development and its association with CHDs.

Purpose of the Study:

• To elucidate the role of HYDIN in cardiac differentiation and heart development.
• To determine the molecular mechanisms underlying HYDIN's function in cardiogenesis.
• To investigate the impact of HYDIN mutations on congenital heart disease risk, specifically atrial septal defects (ASDs).

Main Methods:

• In vitro studies using human embryonic stem cells (hESCs) with HYDIN knockdown, overexpression, and rescue constructs.
• In vivo assessment using shRNA-mediated Hydin knockdown transgenic mice.
• Functional characterization of a common HYDIN variant (c.A2207C) associated with ASD risk in cardiac-differentiating hESCs.

Main Results:

• HYDIN positively regulates human cardiomyocyte differentiation and cardiac contractile gene expression in hESCs.
• HYDIN's function is mediated through GATA4, a key transcription factor in heart development.
• In vivo cardiac-specific HYDIN knockdown in mice resulted in GATA4 downregulation and increased ASD risk; the c.A2207C HYDIN mutation impaired GATA4 expression in hESCs.

Conclusions:

• Loss of HYDIN function inhibits GATA4 expression, thereby increasing atrial septal defect risk.
• This study establishes that a ciliary protein, HYDIN, regulates a critical transcription factor in heart development.
• HYDIN is a novel player in congenital heart disease etiology, particularly ASDs, through its regulation of GATA4.