Abstract
During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. Failure to compact is associated in humans with congenital diseases such as left ventricular non-compaction (LVNC). The mechanisms regulating myocardial compaction are however still poorly understood. Here, we show that deletion of the Ino80 chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. This correlates with defective coronary vascularization, and specific deletion of Ino80 in the two major coronary progenitor tissues—sinus venosus and endocardium—causes intermediate phenotypes. In vitro, endothelial cells promote myocardial expansion independently of blood flow in an Ino80-dependent manner. Ino80 deletion increases the expression of E2F-activated genes and endothelial cell S-phase occupancy. Thus, Ino80 is essential for coronary angiogenesis and allows coronary vessels to support proper compaction of the heart wall.
Highlights
During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation
Compact myocardial growth is promoted by endothelial cells in the absence of blood flow in an Ino80-dependent manner
There were no apparent defects in endothelial-specific knockout hearts prior to coronary vessel development or when the gene was deleted in other cardiac cell types
Summary
The formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. We show that deletion of the Ino[80] chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. The Ino[80] complex has been shown to inhibit embryonic stem cell (ESC) differentiation through the maintenance of ‘open’ chromatin at pluripotent gene promoters[29, 30], and contribute to tumorigenesis by increasing the accessibility of enhancers in cancer cells[31]. These data clearly show important roles for Ino80-mediated chromatin regulation, it is not known whether, in multicellular organisms, it is required in all cells or in specific contexts. Tissue specific deletions of Ino[80] are needed to assess its role during tissue and organ formation
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