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Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells.

Publication ,  Journal Article
Black, JB; Adler, AF; Wang, H-G; D'Ippolito, AM; Hutchinson, HA; Reddy, TE; Pitt, GS; Leong, KW; Gersbach, CA
Published in: Cell Stem Cell
September 1, 2016

Overexpression of exogenous fate-specifying transcription factors can directly reprogram differentiated somatic cells to target cell types. Here, we show that similar reprogramming can also be achieved through the direct activation of endogenous genes using engineered CRISPR/Cas9-based transcriptional activators. We use this approach to induce activation of the endogenous Brn2, Ascl1, and Myt1l genes (BAM factors) to convert mouse embryonic fibroblasts to induced neuronal cells. This direct activation of endogenous genes rapidly remodeled the epigenetic state of the target loci and induced sustained endogenous gene expression during reprogramming. Thus, transcriptional activation and epigenetic remodeling of endogenous master transcription factors are sufficient for conversion between cell types. The rapid and sustained activation of endogenous genes in their native chromatin context by this approach may facilitate reprogramming with transient methods that avoid genomic integration and provides a new strategy for overcoming epigenetic barriers to cell fate specification.

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Published In

Cell Stem Cell

DOI

EISSN

1875-9777

Publication Date

September 1, 2016

Volume

19

Issue

3

Start / End Page

406 / 414

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Transcription Factors
  • Trans-Activators
  • RNA, Guide, CRISPR-Cas Systems
  • Neurons
  • Mice, Inbred C57BL
  • Lentivirus
  • Humans
  • HEK293 Cells
  • Genetic Vectors
 

Citation

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Black, J. B., Adler, A. F., Wang, H.-G., D’Ippolito, A. M., Hutchinson, H. A., Reddy, T. E., … Gersbach, C. A. (2016). Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells. Cell Stem Cell, 19(3), 406–414. https://doi.org/10.1016/j.stem.2016.07.001
Black, Joshua B., Andrew F. Adler, Hong-Gang Wang, Anthony M. D’Ippolito, Hunter A. Hutchinson, Timothy E. Reddy, Geoffrey S. Pitt, Kam W. Leong, and Charles A. Gersbach. “Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells.Cell Stem Cell 19, no. 3 (September 1, 2016): 406–14. https://doi.org/10.1016/j.stem.2016.07.001.
Black JB, Adler AF, Wang H-G, D’Ippolito AM, Hutchinson HA, Reddy TE, et al. Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells. Cell Stem Cell. 2016 Sep 1;19(3):406–14.
Black, Joshua B., et al. “Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells.Cell Stem Cell, vol. 19, no. 3, Sept. 2016, pp. 406–14. Pubmed, doi:10.1016/j.stem.2016.07.001.
Black JB, Adler AF, Wang H-G, D’Ippolito AM, Hutchinson HA, Reddy TE, Pitt GS, Leong KW, Gersbach CA. Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells. Cell Stem Cell. 2016 Sep 1;19(3):406–414.
Journal cover image

Published In

Cell Stem Cell

DOI

EISSN

1875-9777

Publication Date

September 1, 2016

Volume

19

Issue

3

Start / End Page

406 / 414

Location

United States

Related Subject Headings

  • Transcriptional Activation
  • Transcription Factors
  • Trans-Activators
  • RNA, Guide, CRISPR-Cas Systems
  • Neurons
  • Mice, Inbred C57BL
  • Lentivirus
  • Humans
  • HEK293 Cells
  • Genetic Vectors