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Cell. 2017 Sep 21;171(1):103-119.e18. doi: 10.1016/j.cell.2017.09.001.

Non-coding Transcription Instructs Chromatin Folding and Compartmentalization to Dictate Enhancer-Promoter Communication and T Cell Fate.

Author information

1
Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA.
2
Center for Computational Biology & Bioinformatics, Institute for Genomic Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
3
Blood Cell Development and Function, Fox Chase Cancer Center, 333 Cottman Avenue, PA, Philadelphia, PA 19111, USA.
4
Department of Molecular Biology, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: cmurre@ucsd.edu.

Abstract

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.

KEYWORDS:

CTCF; Non-coding transcription; T cell development; cohesin; compartmentalization; leukemia; loop extrusion; lymphoma; phase separation; single-loop domain

PMID:
28938112
PMCID:
PMC5621651
DOI:
10.1016/j.cell.2017.09.001
[Indexed for MEDLINE]
Free PMC Article

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