Epigenetic repressor TRIM28 coordinates myocardial trabeculation and compaction for cardiac chamber formation [RNA-Seq]

RESULTS: TRIM28nCKO mouse embryos died before the age of E16.5 and developed a mid-gestational LVNC phenotype manifested by excessive trabeculation and insufficient myocardial compaction. TRIM28nCKO hearts​ displayed reciprocal​ proliferative profiles: hyperproliferation in the trabecular myocardium versus​ hypoproliferation in the compact layer. Mechanically, TRIM28 depletion in the trabecular myocardium promoted the expression of zinc finger transcription factor of EGR1 (Early Growth Response 1) to increase the deposition of subendocardial extracellular matrix (ECM) and induced the trabecular overgrowth.

In contrast, TRIM28 in the compact layer cooperated with transcription repressor Hey2 to suppress the expression of cell cycle inhibitor P21Cip1/Waf1 (Cyclin-Dependent Kinase Inhibitor 1A) and ensure the normal compaction, whereas TRIM28 ablation disrupted this mechanism and lead to compact insufficiency by removing the inhibition of p21. These distinct compartment-specific mechanisms collectively drive the defective cardiac chamber morphogenesis underlying left ventricular noncompaction (LVNC) in TRIM28 TRIM28nCKO heats.

CONCLUSIONS: Our study identifies TRIM28 and its compartmentalized downstream pathways as the critical epigenetic regulatory axis governing the cardiac chamber development and underlying LVNC pathogenesis.