Non-Coding Transcription Instructs Cohesin-Dependent Chromatin Folding and Compartmentalization to Dictate Enhancer-Promoter Communication and T Cell Fate

• Published in: Cell Vol. 171; no. 1; pp. 103 - 119.e18
• Main Authors: Isoda, Takeshi, Moore, Amanda J, He, Zhaoren, Chandra, Vivek, Aida, Masatoshi, Denholtz, Matthew, van Hamburg, Jan Piet, Fisch, Kathleen M, Chang, Aaron N, Fahl, Shawn, Wiest, David L., Murre, Cornelis
• Format: Journal Article
• Language: English
• Published: 21.09.2017
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.09.001

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. An enhancer RNA called ThymoD facilitates transcription of T cell specific genes by bringing to close proximity the locus control region and promoter of a key lineage-specifying transcription factor.