2012
DOI: 10.1038/nature10953
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Chromatin-modifying enzymes as modulators of reprogramming

Abstract: Generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming involves global epigenetic remodeling1. While several proteins are known to regulate chromatin marks associated with the distinct epigenetic states of cells before and after reprogramming2,3, the role of specific chromatin modifying enzymes in reprogramming remains to be determined. To address how chromatin-modifying proteins influence reprogramming, we used shRNAs to target genes in DNA and histone methylation pathways, and hav… Show more

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Cited by 594 publications
(707 citation statements)
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“…1c), a picomolar, specific, SAM-competitive inhibitor of DOT1L, selectively kills cells bearing MLL chromosomal rearrangements and extends survival in a murine xenograft model of MLL 17 . DOT1L inhibition by EPZ004777 also accelerated reprogramming of somatic cells into induced pluripotent stem cells 18 , suggesting that DOT1L inhibition may be useful in regenerative medicine.…”
mentioning
confidence: 99%
“…1c), a picomolar, specific, SAM-competitive inhibitor of DOT1L, selectively kills cells bearing MLL chromosomal rearrangements and extends survival in a murine xenograft model of MLL 17 . DOT1L inhibition by EPZ004777 also accelerated reprogramming of somatic cells into induced pluripotent stem cells 18 , suggesting that DOT1L inhibition may be useful in regenerative medicine.…”
mentioning
confidence: 99%
“…In this regard, previous studies have uncovered new chromatin-modifying proteins such as DOT1L and YY1 that function as reprogramming repressors. 4 Accordingly, we have provided evidence for a direct regulation of DOT1L and YY1 genes by NF-kB, and a striking over-expression of DOT1L in NGPS fibroblasts, suggesting that these proteins might be relevant effectors of NF-kB role in cellular reprogramming as well as in NF-kB-driven alterations. 2 Additionally, the administration of a specific DOT1L chemical inhibitor remarkably increased the reprogramming efficiency of NGPS fibroblasts.…”
Section: Reprogramming Aging Through Dot1l Inhibitionmentioning
confidence: 66%
“…In particular, VPA enabled human fibroblasts to be reprogrammed with two factors (Oct4 and Sox2) [43], and facilitated the reprogramming of mouse fibroblasts into iPSCs using recombinant proteins of the original reprogramming transcription factors [37]. In addition, parnate (an inhibitor of the H3K4/9 histone demethylase LSD1) and EPZ004777 (an inhibitor of the histone H3K79 methyltransferase DOT1-like) were identified as agents promoting the reprogramming of human cells [46,47]. All these studies suggest that remodeling of the somatic epigenetic landscape represents a major reprogramming barrier.…”
Section: Discovery-based Chemical Approachesmentioning
confidence: 99%