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

Publication ,  Journal Article
Manandhar, D; Song, L; Kabadi, A; Kwon, JB; Edsall, LE; Ehrlich, M; Tsumagari, K; Gersbach, CA; Crawford, GE; Gordân, R
Published in: Nucleic Acids Res
November 16, 2017

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.

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Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

November 16, 2017

Volume

45

Issue

20

Start / End Page

11684 / 11699

Location

England

Related Subject Headings

  • Skin
  • Reverse Transcriptase Polymerase Chain Reaction
  • MyoD Protein
  • Microscopy, Confocal
  • Humans
  • HEK293 Cells
  • Gene Ontology
  • Gene Expression Profiling
  • Fibroblasts
  • Developmental Biology
 

Citation

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Manandhar, D., Song, L., Kabadi, A., Kwon, J. B., Edsall, L. E., Ehrlich, M., … Gordân, R. (2017). Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies. Nucleic Acids Res, 45(20), 11684–11699. https://doi.org/10.1093/nar/gkx773
Manandhar, Dinesh, Lingyun Song, Ami Kabadi, Jennifer B. Kwon, Lee E. Edsall, Melanie Ehrlich, Koji Tsumagari, Charles A. Gersbach, Gregory E. Crawford, and Raluca Gordân. “Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies.Nucleic Acids Res 45, no. 20 (November 16, 2017): 11684–99. https://doi.org/10.1093/nar/gkx773.
Manandhar D, Song L, Kabadi A, Kwon JB, Edsall LE, Ehrlich M, et al. Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies. Nucleic Acids Res. 2017 Nov 16;45(20):11684–99.
Manandhar, Dinesh, et al. “Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies.Nucleic Acids Res, vol. 45, no. 20, Nov. 2017, pp. 11684–99. Pubmed, doi:10.1093/nar/gkx773.
Manandhar D, Song L, Kabadi A, Kwon JB, Edsall LE, Ehrlich M, Tsumagari K, Gersbach CA, Crawford GE, Gordân R. Incomplete MyoD-induced transdifferentiation is associated with chromatin remodeling deficiencies. Nucleic Acids Res. 2017 Nov 16;45(20):11684–11699.
Journal cover image

Published In

Nucleic Acids Res

DOI

EISSN

1362-4962

Publication Date

November 16, 2017

Volume

45

Issue

20

Start / End Page

11684 / 11699

Location

England

Related Subject Headings

  • Skin
  • Reverse Transcriptase Polymerase Chain Reaction
  • MyoD Protein
  • Microscopy, Confocal
  • Humans
  • HEK293 Cells
  • Gene Ontology
  • Gene Expression Profiling
  • Fibroblasts
  • Developmental Biology