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Isoda T , Moore AJ , He Z , Chandra V , Aida M , Denholtz M , Piet van Hamburg J , Fisch KM , Chang AN , Fahl SP , Wiest DL , Murre C
Non-coding Transcription Instructs Chromatin Folding and Compartmentalization to Dictate Enhancer-Promoter Communication and T Cell Fate
Cell. 2017 Sep 21;171(1) :103-119.e18
PMID: 28938112    PMCID: PMC5621651   
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It is now established that Bcl11b specifies T cell fate. Here, we show that in developing T cells, the Bcl11b enhancer repositioned from the lamina to the nuclear interior. Our search for factors that relocalized the Bcl11b enhancer identified a non-coding RNA named ThymoD (thymocyte differentiation factor). ThymoD-deficient mice displayed a block at the onset of T cell development and developed lymphoid malignancies. We found that ThymoD transcription promoted demethylation at CTCF bound sites and activated cohesin-dependent looping to reposition the Bcl11b enhancer from the lamina to the nuclear interior and to juxtapose the Bcl11b enhancer and promoter into a single-loop domain. These large-scale changes in nuclear architecture were associated with the deposition of activating epigenetic marks across the loop domain, plausibly facilitating phase separation. These data indicate how, during developmental progression and tumor suppression, non-coding transcription orchestrates chromatin folding and compartmentalization to direct with high precision enhancer-promoter communication.
1097-4172 Isoda, Takeshi Moore, Amanda J He, Zhaoren Chandra, Vivek Aida, Masatoshi Denholtz, Matthew Piet van Hamburg, Jan Fisch, Kathleen M Chang, Aaron N Fahl, Shawn P Wiest, David L Murre, Cornelis R01 AI109599/AI/NIAID NIH HHS/United States P01 AI102853/AI/NIAID NIH HHS/United States R01 AI100880/AI/NIAID NIH HHS/United States U54 DK107977/DK/NIDDK NIH HHS/United States R01 AI082850/AI/NIAID NIH HHS/United States Journal Article United States Cell. 2017 Sep 21;171(1):103-119.e18. doi: 10.1016/j.cell.2017.09.001.