Super-enhancers(SEs)comprise large clusters of enhancers,which are co-occupied by multiple lineage-specific and master tran-scription factors,and play pivotal roles in regulating gene expression and cell fate determin...Super-enhancers(SEs)comprise large clusters of enhancers,which are co-occupied by multiple lineage-specific and master tran-scription factors,and play pivotal roles in regulating gene expression and cell fate determination.However,it is still largely un-known whether and how SEs are regulated by the noncoding portion of the genome.Here,through genome-wide analysis,wefound that tpng noncoding RNA(IncRNA)genes preferentially lie next to SEs.In mouse embryonic stem cells(mESCs),depletionof$E-associated IlncRNA transcripts dysregulated the activity of their nearby SEs.Specifically,we revealed a critical regulatoryrole of the IncRNA gene Platr22 in modulating the activity of a nearby SE and the expression of the nearby pluripotency regulatorZFP281.Through these regulatory events,Platr22 contributes to pluripotency maintenance and proper differentiation of mESCs.Mechanistically,Platr22 transcripts coat chromatin near the SE region and interact with DDX5 and hnRNP-L.DDX5 further recruitsp300 and other factors related to active transcription.We propose that these factors assemble into a transcription hub,thus pro-moting an open and active epigenetic chromatin state.0ur study highlights an unanticipated role for a class of lncRNAs in epige-netically controlling the activity and vulnerability to perturbation of nearby SEs for cell fate determination.展开更多
基金Grant support is from the National Basic Research Program of China(2017YFA050420A and 2018YFA0107604)the National Natural Science Foundation of China(31630095 and 31925015)+1 种基金the Center for Life Science at Tsinghua UniversityWe thank J.Wang,X.Fu,B.Zhou,and Shen laboratory members for insightful discussion and suggestions.
文摘Super-enhancers(SEs)comprise large clusters of enhancers,which are co-occupied by multiple lineage-specific and master tran-scription factors,and play pivotal roles in regulating gene expression and cell fate determination.However,it is still largely un-known whether and how SEs are regulated by the noncoding portion of the genome.Here,through genome-wide analysis,wefound that tpng noncoding RNA(IncRNA)genes preferentially lie next to SEs.In mouse embryonic stem cells(mESCs),depletionof$E-associated IlncRNA transcripts dysregulated the activity of their nearby SEs.Specifically,we revealed a critical regulatoryrole of the IncRNA gene Platr22 in modulating the activity of a nearby SE and the expression of the nearby pluripotency regulatorZFP281.Through these regulatory events,Platr22 contributes to pluripotency maintenance and proper differentiation of mESCs.Mechanistically,Platr22 transcripts coat chromatin near the SE region and interact with DDX5 and hnRNP-L.DDX5 further recruitsp300 and other factors related to active transcription.We propose that these factors assemble into a transcription hub,thus pro-moting an open and active epigenetic chromatin state.0ur study highlights an unanticipated role for a class of lncRNAs in epige-netically controlling the activity and vulnerability to perturbation of nearby SEs for cell fate determination.
