Polycomb-Repressed Genes Have Permissive Enhancers that Initiate Reprogramming

• Published in: Cell 2011-12, Vol.147 (6), p.1283-1294
• Main Authors: Taberlay, Phillippa C., Kelly, Theresa K., Liu, Chun-Chi, You, Jueng Soo, De Carvalho, Daniel D., Miranda, Tina B., Zhou, Xianghong J., Liang, Gangning, Jones, Peter A.
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chromatin; Enhancer Elements, Genetic; Epigenomics; Fibroblasts - metabolism; Humans; Mice; MyoD Protein - genetics; Nucleosomes - metabolism; Octamer Transcription Factor-3 - metabolism; Polycomb-Group Proteins; Promoter Regions, Genetic; regulator genes; Repressor Proteins - metabolism; stem cells; transcription; transcription factors
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2011.10.040

Key regulatory genes, suppressed by Polycomb and H3K27me3, become active during normal differentiation and induced reprogramming. Using the well-characterized enhancer/promoter pair of MYOD1 as a model, we have identified a critical role for enhancers in reprogramming. We observed an unexpected nucleosome-depleted region (NDR) at the H3K4me1-enriched enhancer at which transcriptional regulators initially bind, leading to subsequent changes in the chromatin at the cognate promoter. Exogenous Myod1 activates its own transcription by binding first at the enhancer, leading to an NDR and transcription-permissive chromatin at the associated MYOD1 promoter. Exogenous OCT4 also binds first to the permissive MYOD1 enhancer but has a different effect on the cognate promoter, where the monovalent H3K27me3 marks are converted to the bivalent state characteristic of stem cells. Genome-wide, a high percentage of Polycomb targets are associated with putative enhancers in permissive states, suggesting that they may provide a widespread avenue for the initiation of cell-fate reprogramming. [Display omitted] [Display omitted] ► Master transcriptional regulators initiate reprogramming through enhancers ► Reprogramming can be forced in multiple directions, through a single enhancer ► A bivalent promoter is established by ectopic OCT4 binding first to the enhancer ► Genome-wide, many PRC-marked promoters have enhancers in permissive states Binding of transcription factors to enhancers, not promoters, initiates cell-fate reprogramming. Chromatin changes at the cognate promoter follow enhancer binding, leading to a cell-fate switch.