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Mol Cell. 2017 Apr 6;66(1):102-116.e7. doi: 10.1016/j.molcel.2017.02.027.

The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries.

Author information

1
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
4
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA.
5
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jcremins@seas.upenn.edu.
6
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: blobel@email.chop.edu.

Abstract

Bromodomain and extraterminal motif (BET) proteins are pharmacologic targets for the treatment of diverse diseases, yet the roles of individual BET family members remain unclear. We find that BRD2, but not BRD4, co-localizes with the architectural/insulator protein CCCTC-binding factor (CTCF) genome-wide. CTCF recruits BRD2 to co-bound sites whereas BRD2 is dispensable for CTCF occupancy. Disruption of a CTCF/BRD2-occupied element positioned between two unrelated genes enables regulatory influence to spread from one gene to another, suggesting that CTCF and BRD2 form a transcriptional boundary. Accordingly, single-molecule mRNA fluorescence in situ hybridization (FISH) reveals that, upon site-specific CTCF disruption or BRD2 depletion, expression of the two genes becomes increasingly correlated. HiC shows that BRD2 depletion weakens boundaries co-occupied by CTCF and BRD2, but not those that lack BRD2. These findings indicate that BRD2 supports boundary activity, and they raise the possibility that pharmacologic BET inhibitors can influence gene expression in part by perturbing domain boundary function.

KEYWORDS:

BET proteins; BRD2; CTCF; chromatin architecture; transcription

PMID:
28388437
PMCID:
PMC5393350
DOI:
10.1016/j.molcel.2017.02.027
[Indexed for MEDLINE]
Free PMC Article

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