Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies.

Autor:	Manandhar D; Program in Computational Biology and Bioinformatics, Duke University, Durham, NC 27708, USA.; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA., Song L; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; Department of Pediatrics, Medical Genetics Division, Duke University, Durham, NC 27708, USA., Kabadi A; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA., Kwon JB; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; University Program in Genetics and Genomics, Duke University, Durham, NC 27708, USA., Edsall LE; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; University Program in Genetics and Genomics, Duke University, Durham, NC 27708, USA., Ehrlich M; Hayward Genetics Center, Tulane Health Sciences Center, New Orleans, LA 70112, USA.; Tulane Cancer Center, and Center for Bioinformatics and Genomics, Tulane Health Sciences Center, New Orleans, LA 70112, USA., Tsumagari K; Hayward Genetics Center, Tulane Health Sciences Center, New Orleans, LA 70112, USA., Gersbach CA; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA., Crawford GE; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; Department of Pediatrics, Medical Genetics Division, Duke University, Durham, NC 27708, USA., Gordân R; Center for Genomic and Computational Biology, Duke University, Durham, NC 27708, USA.; Departments of Biostatistics and Bioinformatics, Computer Science, and Molecular Genetics and Microbiology, Duke University, Durham NC 27708, USA.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2017 Nov 16; Vol. 45 (20), pp. 11684-11699.
DOI:	10.1093/nar/gkx773
Abstrakt:	Our current understanding of cellular transdifferentiation systems is limited. It is oftentimes unknown, at a genome-wide scale, how much transdifferentiated cells differ quantitatively from both the starting cells and the target cells. Focusing on transdifferentiation of primary human skin fibroblasts by forced expression of myogenic transcription factor MyoD, we performed quantitative analyses of gene expression and chromatin accessibility profiles of transdifferentiated cells compared to fibroblasts and myoblasts. In this system, we find that while many of the early muscle marker genes are reprogrammed, global gene expression and accessibility changes are still incomplete when compared to myoblasts. In addition, we find evidence of epigenetic memory in the transdifferentiated cells, with reminiscent features of fibroblasts being visible both in chromatin accessibility and gene expression. Quantitative analyses revealed a continuum of changes in chromatin accessibility induced by MyoD, and a strong correlation between chromatin-remodeling deficiencies and incomplete gene expression reprogramming. Classification analyses identified genetic and epigenetic features that distinguish reprogrammed from non-reprogrammed sites, and suggested ways to potentially improve transdifferentiation efficiency. Our approach for combining gene expression, DNA accessibility, and protein-DNA binding data to quantify and characterize the efficiency of cellular transdifferentiation on a genome-wide scale can be applied to any transdifferentiation system. (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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