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.
journal_name
Cell Stem Celljournal_title
Cell stem cellauthors
Stone NR,Gifford CA,Thomas R,Pratt KJB,Samse-Knapp K,Mohamed TMA,Radzinsky EM,Schricker A,Ye L,Yu P,van Bemmel JG,Ivey KN,Pollard KS,Srivastava Ddoi
10.1016/j.stem.2019.06.012subject
Has Abstractpub_date
2019-07-03 00:00:00pages
87-102.e9issue
1eissn
1934-5909issn
1875-9777pii
S1934-5909(19)30276-0journal_volume
25pub_type
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