The H2Bub1-deposition complex is required for human and mouse cardiogenesis

Area of Science:

• Epigenetics
• Developmental Biology
• Cardiovascular Research

Background:

• De novo variants in histone H2B monoubiquitylation (H2Bub1) are linked to congenital heart disease.
• H2Bub1 plays roles in stem cell differentiation, cilia function, cardiomyocyte maturation, and transcriptional elongation.
• The precise role of H2Bub1 in cardiogenesis remains unclear.

Purpose of the Study:

• To investigate the role of H2Bub1 and its deposition complex in mouse cardiogenesis and human cardiomyocyte differentiation.
• To elucidate how H2Bub1 distribution affects gene expression during cardiomyocyte development.

Main Methods:

• Analysis of H2Bub1 marks during human induced pluripotent stem cell (iPSC) differentiation into cardiomyocytes.
• Generation of mice with cardiac-specific Rnf20 deletion to assess its role in cardiogenesis.
• Quantification of full-length transcripts for cardiac-specific genes in iPSC-derived cardiomyocytes with altered H2Bub1 levels.

Main Results:

• The H2Bub1 deposition complex (RNF20-RNF40-UBE2B) is essential for mouse cardiogenesis and human iPSC-cardiomyocyte differentiation.
• Cardiac-specific Rnf20 deletion in mice leads to embryonic lethality and myocardial abnormalities.
• H2Bub1 is dynamically regulated during cardiomyocyte differentiation, preserved on key cardiac-specific genes, and its reduction impairs full-length transcript production.

Conclusions:

• Normal H2Bub1 distribution is indispensable for proper cardiogenesis and cardiomyocyte differentiation.
• H2Bub1 regulates tissue-specific gene expression, likely by promoting the production of full-length transcripts.