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Cell Stem Cell. 2019 Jul 3;25(1):87-102.e9. doi: 10.1016/j.stem.2019.06.012.

Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming.

Author information

1
Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, CA 94143, USA.
2
Gladstone Institutes, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
3
Gladstone Institutes, San Francisco, CA 94158, USA.
4
Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, CA 94143, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA.
5
Gladstone Institutes, San Francisco, CA 94158, USA; Department of Epidemiology & Biostatistics, University of California, San Francisco, CA 94143, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA. Electronic address: katherine.pollard@gladstone.ucsf.edu.
6
Gladstone Institutes, San Francisco, CA 94158, USA; Departments of Pediatrics and Biochemistry & Biophysics, University of California, San Francisco, CA 94143, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA. Electronic address: dsrivastava@gladstone.ucsf.edu.

Abstract

Ectopic expression of combinations of transcription factors (TFs) can drive direct lineage conversion, thereby reprogramming a somatic cell's identity. To determine the molecular mechanisms by which Gata4, Mef2c, and Tbx5 (GMT) induce conversion from a cardiac fibroblast toward an induced cardiomyocyte, we performed comprehensive transcriptomic, DNA-occupancy, and epigenomic interrogation throughout the reprogramming process. Integration of these datasets identified new TFs involved in cardiac reprogramming and revealed context-specific roles for GMT, including the ability of Mef2c and Tbx5 to independently promote chromatin remodeling at previously inaccessible sites. We also find evidence for cooperative facilitation and refinement of each TF's binding profile in a combinatorial setting. A reporter assay employing newly defined regulatory elements confirmed that binding of a single TF can be sufficient for gene activation, suggesting that co-binding events do not necessarily reflect synergy. These results shed light on fundamental mechanisms by which combinations of TFs direct lineage conversion.

KEYWORDS:

ATAC-seq; ChIP-seq; cardiac fibroblast; cardiomyocyte; reprogramming; single-cell RNA-seq; transcription factor

PMID:
31271750
PMCID:
PMC6632093
[Available on 2020-07-03]
DOI:
10.1016/j.stem.2019.06.012

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