Journal
CELL STEM CELL
Volume 19, Issue 3, Pages 406-414Publisher
CELL PRESS
DOI: 10.1016/j.stem.2016.07.001
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Funding
- US NIH [R01DA036865, U01HG007900]
- NIH Director's New Innovator Award [DP2OD008586]
- National Science Foundation (NSF) Faculty Early Career Development (CAREER) Award [CBET-1151035]
- NIH [P30AR066527]
- NIH Biotechnology Training Grant [T32GM008555]
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [1151035] Funding Source: National Science Foundation
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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 transientmethods that avoid genomic integration and provides a new strategy for overcoming epigenetic barriers to cell fate specification.
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