Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming
| Autor: | Reuben Thomas, Karishma Pratt, Kaitlen Samse-Knapp, Lin Ye, Ethan Radzinsky, Joke G. van Bemmel, Nicole Stone, Kathryn N. Ivey, Casey A. Gifford, Amelia Schricker, Tamer M.A. Mohamed, Pengzhi Yu, Deepak Srivastava, Katherine S. Pollard |
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| Rok vydání: | 2019 |
| Předmět: |
ATAC-seq
cardiomyocyte Cardiovascular Medical and Health Sciences Epigenesis Genetic Machine Learning Mice 0302 clinical medicine MEF2C Myocytes Cardiac Cells Cultured transcription factor Epigenomics Regulation of gene expression 0303 health sciences Cultured single-cell RNA-seq MEF2 Transcription Factors Cell Differentiation Biological Sciences Cellular Reprogramming Cell biology ChIP-seq Heart Disease Molecular Medicine Reprogramming Cardiac Protein Binding Biotechnology Transcriptional Activation Cells Biology Chromatin remodeling Article 03 medical and health sciences Genetic Genetics Animals Cell Lineage Transcription factor 030304 developmental biology Myocytes Human Genome cardiac fibroblast reprogramming Cell Biology Chromatin Assembly and Disassembly GATA4 Transcription Factor Ectopic expression T-Box Domain Proteins 030217 neurology & neurosurgery Epigenesis Developmental Biology |
| Zdroj: | Cell stem cell, vol 25, iss 1 Cell Stem Cell Stone, N R, Gifford, C A, Thomas, R, Pratt, K J B, Samse-Knapp, K, Mohamed, T M A, Radzinsky, E M, Schricker, A, Ye, L, Yu, P, van Bemmel, J G, Ivey, K N, Pollard, K S & Srivastava, D 2019, ' Context-Specific Transcription Factor Functions Regulate Epigenomic and Transcriptional Dynamics during Cardiac Reprogramming ', Cell Stem Cell, vol. 25, no. 1, pp. 87-102.e9 . https://doi.org/10.1016/j.stem.2019.06.012 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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