Title | Targeted Epigenetic Remodeling of Endogenous Loci by CRISPR/Cas9-Based Transcriptional Activators Directly Converts Fibroblasts to Neuronal Cells. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Black, JB, Adler, AF, Wang, H-G, D'Ippolito, AM, Hutchinson, HA, Reddy, TE, Pitt, GS, Leong, KW, Gersbach, CA |
Journal | Cell Stem Cell |
Volume | 19 |
Issue | 3 |
Pagination | 406-14 |
Date Published | 2016 Sep 01 |
ISSN | 1875-9777 |
Abstract | 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. |
DOI | 10.1016/j.stem.2016.07.001 |
Alternate Journal | Cell Stem Cell |
PubMed ID | 27524438 |
PubMed Central ID | PMC5010447 |
Grant List | T32 GM008555 / GM / NIGMS NIH HHS / United States DP2 OD008586 / OD / NIH HHS / United States T32 GM007754 / GM / NIGMS NIH HHS / United States R01 DA036865 / DA / NIDA NIH HHS / United States U01 HG007900 / HG / NHGRI NIH HHS / United States P30 AR066527 / AR / NIAMS NIH HHS / United States |