Transcription factor EBF1 non-cell autonomously regulates cardiac growth and differentiation.

Reciprocal interactions between non-myocytes and cardiomyocytes regulate cardiac growth and differentiation. Here, we report that transcription factor Ebf1 is highly expressed in non-myocytes and potently regulates heart development. Ebf1 deficient hearts display myocardial hypercellularity and reduced cardiomyocyte size, ventricular conduction system hypoplasia and conduction system disease. Growth abnormalities in Ebf1 knockout hearts are observed as early as embryonic day 13.5. Transcriptional profiling of Ebf1-deficient embryonic cardiac non-myocytes demonstrates dysregulation of Polycomb repressive complex 2 targets and ATAC-Seq reveals altered chromatin accessibility near many of these same genes. Gene set enrichment analysis of differentially expressed genes in cardiomyocytes isolated from E13.5 hearts of wildtype and mutant mice reveals significant enrichment of MYC targets, and consistent with this finding, we observe increased abundance of MYC in mutant hearts. EBF1-deficient non-myocytes, but not wildtype non-myocytes, are sufficient to induce excessive accumulation of MYC in co-cultured wildtype cardiomyocytes. Finally, we demonstrate that BMP signaling induces Ebf1 expression in embryonic heart cultures and controls a gene program enriched in EBF1 targets. These data reveal a novel non-cell autonomous pathway controlling cardiac growth and differentiation.