TY - JOUR
T1 - The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries
AU - Hsu, Sarah C.
AU - Gilgenast, Thomas G.
AU - Bartman, Caroline R.
AU - Edwards, Christopher R.
AU - Stonestrom, Aaron J.
AU - Huang, Peng
AU - Emerson, Daniel J.
AU - Evans, Perry
AU - Werner, Michael T.
AU - Keller, Cheryl A.
AU - Giardine, Belinda
AU - Hardison, Ross C.
AU - Raj, Arjun
AU - Phillips-Cremins, Jennifer E.
AU - Blobel, Gerd A.
N1 - Funding Information:
We thank members of the lab for helpful discussion and critical comments on the manuscript. This work was supported by an NCI F30 (F30CA189553) fellowship and Patel Family Scholar Award to S.C.H.; an NIH GRFP fellowship to C.R.B.; 5T32HL007439-37 to M.T.W.; R56DK065806 and U54HG006998 to R.C.H.; an NIH New Innovator Award 1DP2OD008514 to A.R.; 1RO1DK54937 to G.A.B.; R24DK106766 to G.A.B. and R.C.H.; U01HL129998A to A.R., G.A.B., and J.E.P.-C.; the Alfred P. Sloan Foundation (FR-2015-65238; to J.E.P.-C.); a joint NSF-NIGMS grant (1562665) to support research at the interface of the biological and mathematical sciences to J.E.P.-C.; and a generous gift from the DiGaetano family to G.A.B. J.E.P.-C. is a New York Stem Cell Foundation (NYSCF) Robertson Investigator.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/4/6
Y1 - 2017/4/6
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2017.02.027
DO - 10.1016/j.molcel.2017.02.027
M3 - Article
C2 - 28388437
AN - SCOPUS:85017116447
SN - 1097-2765
VL - 66
SP - 102-116.e7
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -