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

Sarah C. Hsu, Thomas G. Gilgenast, Caroline R. Bartman, Christopher R. Edwards, Aaron J. Stonestrom, Peng Huang, Daniel J. Emerson, Perry Evans, Michael T. Werner, Cheryl A. Keller, Belinda Giardine, Ross C. Hardison, Arjun Raj, Jennifer E. Phillips-Cremins, Gerd A. Blobel

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)102-116.e7
JournalMolecular cell
Volume66
Issue number1
DOIs
StatePublished - Apr 6 2017

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Amino Acid Motifs
Gene Expression
Regulator Genes
Protein Binding
Fluorescence
Genome
Messenger RNA
Genes
CCCTC-binding factor

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Hsu, S. C., Gilgenast, T. G., Bartman, C. R., Edwards, C. R., Stonestrom, A. J., Huang, P., ... Blobel, G. A. (2017). The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries. Molecular cell, 66(1), 102-116.e7. https://doi.org/10.1016/j.molcel.2017.02.027
Hsu, Sarah C. ; Gilgenast, Thomas G. ; Bartman, Caroline R. ; Edwards, Christopher R. ; Stonestrom, Aaron J. ; Huang, Peng ; Emerson, Daniel J. ; Evans, Perry ; Werner, Michael T. ; Keller, Cheryl A. ; Giardine, Belinda ; Hardison, Ross C. ; Raj, Arjun ; Phillips-Cremins, Jennifer E. ; Blobel, Gerd A. / The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries. In: Molecular cell. 2017 ; Vol. 66, No. 1. pp. 102-116.e7.
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Hsu, SC, Gilgenast, TG, Bartman, CR, Edwards, CR, Stonestrom, AJ, Huang, P, Emerson, DJ, Evans, P, Werner, MT, Keller, CA, Giardine, B, Hardison, RC, Raj, A, Phillips-Cremins, JE & Blobel, GA 2017, 'The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries', Molecular cell, vol. 66, no. 1, pp. 102-116.e7. https://doi.org/10.1016/j.molcel.2017.02.027

The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries. / Hsu, Sarah C.; Gilgenast, Thomas G.; Bartman, Caroline R.; Edwards, Christopher R.; Stonestrom, Aaron J.; Huang, Peng; Emerson, Daniel J.; Evans, Perry; Werner, Michael T.; Keller, Cheryl A.; Giardine, Belinda; Hardison, Ross C.; Raj, Arjun; Phillips-Cremins, Jennifer E.; Blobel, Gerd A.

In: Molecular cell, Vol. 66, No. 1, 06.04.2017, p. 102-116.e7.

Research output: Contribution to journalArticle

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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.

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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Hsu SC, Gilgenast TG, Bartman CR, Edwards CR, Stonestrom AJ, Huang P et al. The BET Protein BRD2 Cooperates with CTCF to Enforce Transcriptional and Architectural Boundaries. Molecular cell. 2017 Apr 6;66(1):102-116.e7. https://doi.org/10.1016/j.molcel.2017.02.027