Genetic Variation in Enhancers Modifies Cardiomyopathy Gene Expression and Progression

Area of Science:

• Cardiovascular Genetics
• Epigenomics
• Molecular Cardiology

Background:

• Cardiomyopathy phenotypes vary due to genetic and non-genetic factors, with gene expression regulated by promoters and enhancers.
• Human genetic variations in these regulatory elements may explain observed variability in cardiomyopathy progression and outcomes.

Purpose of the Study:

• To identify and functionally validate enhancers for cardiomyopathy genes MYH7 and LMNA.
• To investigate the role of genomic variation within enhancers in cardiomyopathy progression.

Main Methods:

• Epigenomic profiling, including promoter-capture chromatin conformation, was used to identify enhancers for MYH7 and LMNA.
• Enhancer function was validated in human induced pluripotent stem cell-derived cardiomyocytes.
• Genome-wide analysis identified variants in enhancers potentially affecting cardiac gene expression, with one variant correlated to cardiomyopathy progression using biobank data.

Main Results:

• Multiple enhancers for LMNA and MYH7 were identified and validated, including one regulating the MYH6 to MYH7 expression switch.
• Deletion of a key enhancer increased MYH6 expression and contractile rate in engineered heart tissue.
• A specific variant (rs875908) disrupting a transcription factor binding site in an enhancer near MYH7 was identified; gene editing reduced MYH7 expression, and this variant associated with cardiomyopathy progression.

Conclusions:

• Enhancers play a crucial role in regulating cardiomyopathy gene expression.
• Genomic variations within enhancer regions are associated with the progression of cardiomyopathy.
• This integrated approach successfully identified noncoding modifiers of cardiomyopathy, applicable to other cardiac genes.