Chromatin Modifying Enzymes as Modulators of Reprogramming

DSpace/Manakin Repository

Chromatin Modifying Enzymes as Modulators of Reprogramming

Citable link to this page

 

 
Title: Chromatin Modifying Enzymes as Modulators of Reprogramming
Author: Onder, Tamer T.; Kara, Nergis; Sinha, Amit U.; Bernt, Kathrin M.; Mancarci, Ogan. B.; Gupta, Piyush B.; Cherry, Anne Blanche Cresswell; Zhu, Nan; Cahan, Patrick; Unternaehrer, Juli; Lander, Eric Steven; Armstrong, Scott A.; Daley, George Quentin

Note: Order does not necessarily reflect citation order of authors.

Citation: Onder, Tamer T., Nergis Kara, Anne Blanche Cresswell Cherry, Amit U. Sinha, Nan Zhu, Kathrin M. Bernt, Patrick Cahan, et al. 2012. Chromatin modifying enzymes as modulators of reprogramming. Nature 483(7391): 598-602.
Full Text & Related Files:
Abstract: Generation of induced pluripotent stem cells (iPSCs) by somatic cell reprogramming involves global epigenetic remodeling. While several proteins are known to regulate chromatin marks associated with the distinct epigenetic states of cells before and after reprogramming, 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 have identified positive and negative modulators of iPSC generation. While inhibition of the core components of the polycomb repressive complex 1 and 2, including the histone 3 lysine 27 methyltransferase Ezh2, reduced reprogramming efficiency, suppression of SUV39H1, YY1, and Dot1L enhanced reprogramming. Specifically, inhibition of the H3K79 histone methyltransferase Dot1L by shRNA or a small molecule accelerated reprogramming, significantly increased the yield of iPSC colonies, and substituted for Klf4 and c-Myc. Inhibition of Dot1L early in the reprogramming process is associated with a marked increase in two alternative factors, Nanog and Lin28, which play essential functional roles in the enhancement of reprogramming. Genome-wide analysis of H3K79me2 distribution revealed that fibroblast-specific genes associated with the epithelial to mesenchymal transition lose H3K79me2 in the initial phases of reprogramming. Dot1L inhibition facilitates the loss of this mark from genes that are fated to be repressed in the pluripotent state. These findings implicate specific chromatin-modifying enzymes as barriers to or facilitators of reprogramming, and demonstrate how modulation of chromatin-modifying enzymes can be exploited to more efficiently generate iPSCs with fewer exogenous transcription factors.
Published Version: doi:10.1038/nature10953
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3501145/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10591010
Downloads of this work:

Show full Dublin Core record

This item appears in the following Collection(s)

 
 

Search DASH


Advanced Search
 
 

Submitters