Cardiac Reprogramming Factors Synergistically Activate Genome-wide Cardiogenic Stage-Specific Enhancers

Abstract

SUMMARY The cardiogenic transcription factors (TFs) Mef2c, Gata4, and Tbx5 can directly reprogram fibroblasts to induced cardiac-like myocytes (iCLMs), presenting a potential source of cells for cardiac repair. While activity of these TFs is enhanced by Hand2 and Akt1, their genomic targets and interactions during reprogramming are not well studied. We performed genome-wide analyses of cardiogenic TF binding and enhancer profiling during cardiac reprogramming. We found that these TFs synergistically activate enhancers highlighted by Mef2c binding sites and that Hand2 and Akt1 coordinately recruit other TFs to enhancer elements. Intriguingly, these enhancer landscapes collectively resemble patterns of enhancer activation during embryonic cardiogenesis. We further constructed a cardiac reprogramming gene regulatory network and found repression of EGFR signaling pathway genes. Consistently, chemical inhibition of EGFR signaling augmented reprogramming. Thus, by defining epigenetic landscapes these findings reveal synergistic transcriptional activation across a broad landscape of cardiac enhancers and key signaling pathways that govern iCLM reprogramming.

Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

“…Additionally, transgenic mouse embryos carrying a lacZ reporter driven by this enhancer showed beta-galactosidase activity specific to the heart at E11.5, confirming this sequence as a bona fide cardiac developmental enhancer (Fig. 4E), which we have further characterized in a recent publication (29). Together, these data uncover an embryonic developmental gene program that is transiently retained in the neonatal heart.…”

The genetic structure and adaptation of Andean highlanders and Amazonian dwellers is influenced by the interplay between geography and culture

“…HAND2-AS1 is located in the antisense 5' region of HAND2 and contains 2 enhancers for this gene. A natural selection genome-wide scan 36 identified three genes related to the cardiovascular system in Andeans, including TBX5, which works together with HAND2 in reprogramming fibroblasts to cardiac-like myocytes 40,41 . This information suggests (but does not demonstrate) that HAND2-AS1 signature of natural selection is related with cardiovascular adaptations.…”

BRD4 Interacts with GATA4 to Govern Mitochondrial Homeostasis in Adult Cardiomyocytes

“…GATA4 is a well-established lineage determining TF for CMs whose role in cardiac development and human congenital heart disease has been extensively studied by our group and others 50,51 . As ectopic Gata4 expression (along with Mef2c and Tbx5; GMT) can induce conversion of cardiac fibroblasts into induced CMs 52-54 , much effort has also focused on the molecular mechanisms by which GATA4 regulates cellular identity 55,56 . In the adult heart, GATA4 plays an important role in stress responsiveness and regulation of pro-angiogenic genes 57,58 .…”