The polycomb protein complex interacts with GATA-6/PPARα to inhibit α-MHC expression.

Transcription factors collaborate with epigenetic regulatory factors to orchestrate cardiac differentiation for heart development, but the underlying mechanism is not fully understood. Here, we report that GATA-6 induces cardiac differentiation but peroxisome proliferator-activated receptor α (PPARα) reverses GATA-6-induced cardiac differentiation, possibly because GATA-6/PPARα recruits the polycomb protein complex containing EZH2/Ring1b/BMI1 to the promoter of the cardiac-specific α-myosin heavy chain (α-MHC) gene and suppresses α-MHC expression, which ultimately inhibits cardiac differentiation. Furthermore, Ring1b ubiquitylates PPARα and GATA-6. By overexpression and knockout of EZH2/BMI1, it was demonstrated that the polycomb protein complex inhibits cardiac differentiation induced by GATA-6 and PPARα. Together, our results demonstrate that the polycomb protein complex interacts with GATA-6/PPARα to inhibit cardiac differentiation, a finding that could facilitate the development of new therapies for congenital heart disease.