Brian Strahl

Research: Histone modifications and epigenetics

Brian Strahl

Professor and Vice-Chair
Faculty Director, UNC High-throughput Peptide Synthesis and Array Facility
(PhD - NC State University)

120 Mason Farm Road, CB# 7260
3060 Genetic Medicine
Chapel Hill, NC 27599-7260
919-843-3896

Strahl Lab Website

HONORS & AWARDS

  • Phillip & Ruth Hettleman Prize - 2009
  • NIH Eureka Award - 2008
  • Schering-Plough Research Institute Award - 2004
  • Presidential Early Career Award for Scientists and Engineers - 2003
  • Pew Scholar - 2003

RESEARCH

Histone Modifications and Gene Regulation

Eukaryotic genomes are highly condensed through their interaction with histone proteins. Such compaction results in the restricted access of proteins to the DNA template.Strahl graphic Thus, a significant question to ask is how chromatin environments are established and maintained, as well as made permissive to the protein machineries that drive transcription, replication, recombination, and repair. One mechanism known to regulate chromatin structure and function are histone post-translational modifications. A wide number of modifications, such as acetylation and methylation, decorate the histone proteins and studies indicate that they work together in the form of a ‘histone code’ to regulate chromatin-based activities.

In our laboratory, we have been exploring the role of histone-modifying enzymes in RNA polymerase II (RNAPII) transcription. Our lab has contributed to the finding that a variety of enzymes that either methylate, acetylate or ubiquitylate histones, contribute to transcription elongation and are associated with the elongating form of RNAPII.  Current efforts are aimed at understanding how these enzymes (and their modifications) contribute to chromatin organization, gene regulation and how their dysregulation leads to cancer.  In addition to our studies into gene regulation, our lab is also engaged in a high-throughput proteomics project involving histone peptide arrays to decipher how histone modifications, and the histone codes they generate, regulate the recruitment of chromatin-associated proteins that govern the diverse functions associated with DNA.

Core Techniques: www.med.unc.edu/biochem/unc-peptides

  • Yeast genetics
  • Protein Purification
  • Peptide Synthesis
  • Peptide Arrays
  • Mammalian Cell Culture

RECENT PUBLICATIONS  pubmed.png (click for Full Publication List)

2016

Harrison, J. S., Cornett, E. M., Goldfarb, D., DaRosa, P. A., Li, Z. M., Yan, F., Dickson, B. M., Guo, A. H., Cantu, D. V., Kaustov, L., Brown, P. J., Arrowsmith, C. H., Klevit, R. E., Erie, D. A., Major, M. B., Krajewski, K., Kuhlman, B., Strahl, B. D. & Rothbart, S. B. (2016) Hemi-methylated DNA regulates DNA methylation inheritance through allosteric control of H3 ubiquitylation by UHRF1. ELife. (In Press).

Penke, T. J. R., McKay, D. J., Strahl, B. D., Matera, A. G & Duronio, R. J. (2016) Direct interrogation of the role of H3K9 in metazoan heterochromatin function. Genes & Development. (In Press).

Chen, H., Workman, J. J., Strahl, B. D. & Laribee, R. N. (2016) Histone H3 and TORC1 Prevent Organelle Dysfunction and Cell Death by Promoting Nuclear Retention of HMGB Proteins. Epigenetics & Chromatin. 9:34

Hacker, K. E.*, Fahey, C. C.*, Shinsky, S. A.*, Chiang, Y.-C. J.*, DiFiore, J. V.*, Jha, D. K., Vo, A. H., Shavit, J. A. Davis, I, J., Strahl, B. D.* & Rathmell, W. K.* (2016) Structure/Function Analysis of Recurrent Mutations in SETD2 Reveals a Critical and Conserved Role for a SET Domain Residue in Maintaining Protein Stability and H3K36 Trimethylation. Journal of Biological Chemistry. Aug 15. pii: jbc.M116.739375.

Andrews, F. H., Strahl, B. D. & Kutateladze, T. G. (2016) Insights into newly discovered marks and readers of epigenetic information. Nature Chemical Biology. 12:662-668.

Cornett, E. M., Dickson, B. M., Vaughan, R. M., Trievel, R. C., Strahl, B. D. & Rothbart, S. B. (2016) Substrate specificity profiling of histone-modifying enzymes by peptide microarray. Methods in Enzymology. 574:31-52.

McDaniel, S. L., Fligor, J. E., Chun, R., Cui, H., Bridgers, J. B., DiFiore, J. V., Guo, A. H., Li, B. & Strahl, B. D. (2016) Combinatorial Histone Readout by the Dual Plant Homeodomain (PHD) Fingers of Rco1 Mediates Rpd3S Chromatin Recruitment and the Maintenance of Transcriptional Fidelity. Journal of Biological Chemistry. 291:14796-14802.

Bedard, L. G., Dronamraju, R., Kerschner, J.L., Hunter, G.O., Axley, E.D., Boyd, A.K., Strahl, B.D. & Mosley, A.L. (2016) Quantitative analysis of dynamic protein interactions during transcription reveals a role for casein kinase II in PAF complex phosphorylation and regulation of H2B monoubiquitylation. Journal of Biological Chemistry. 291:13410-13420.

Yumerefendi, H., Lerner, A. M., Zimmerman, S. P., Hahn, K., Bear, J. E., Strahl, B. D. & Kuhlman, B. (2016) Light-induced nuclear export reveals rapid dynamics of epigenetic marks. Nature Chemical Biology. 12:399-401.

Andrews, F. H.*, Shinsky, A. S.*, Shanle, E. K., Bridgers, J. B., Gest, A., Tsun, I. K., Krajewski, K., Shi, X., Strahl, B. D.* & Kutateladze, T. G.* (2016) The Taf14 YEATS domain is a reader of histone crotonylation. Nature Chemical Biology12:396-398.

Gatchalian, J., Mora, C., Shinsky, S. A., Ospina, R. R., Mansilla, A. L., Klein, B. J., Andrews, F. H., Strahl, B. D., van Wely, K. H. M. & Kutateladze, T. G. (2016) Chromatin condensation and recruitment of PHD fingers to histone H3K4me3 are mutually exclusive. Nucleic Acids Research. Mar 25. pii: gkw193.

Sorenson, M. R., Jha, D. K., Ucles, S., Flood, D., Strahl, B. D., Stevens, S. W. & Kress, T. L. (2016) Histone H3K36 methylation regulates pre-mRNA splicing in Saccharomyces cerevisiae. RNA Biology. 13:412-426.

Hattori, T., Lai, D., Dementieva, I. S., Montano, S. P., Zheng, Y., Akin, L., Swift, K., M., Grzybowski, A. T., Koide, A., Krajewski, K., Strahl, B. D., Kelleher, N. L., Ruthenburg, A. J. & Koide, S. (2016) Antigen clasping by two antigen-binding sites of an exceptionally specific antibody for histone methylation. Proc Natl Acad Sci USA.113:2092-2097.

Andrews, F. H.*, Shanle, E. K.*, Strahl, B. D.* & Kutateladze, T. G.* (2016) The essential role of acetyllysine binding by the YEATS domain in transcriptional regulation. Transcription. 7:14-20.

Andrews, F. H., Gatchalian, J., Krajewski, K., Strahl, B. D. & Kutateladze, T. G. (2016) Regulation of methyllysine readers through phosphorylation. ACS Chemical Biology. 7:14-20.

Shanle, E. K., Tsun, I. K. & Strahl, B. D. (2016) A course-based undergraduate research experience investigating p300 bromodomain mutations. Biochemistry and Molecular Biology Education. 44:68-74.

2015

Cliffe, A. R., Vogel, J. L., Arbuckle, J. H., Geden, M. J., Rothbart, S. B., Cusack, C. L., Strahl, B. D., Kristie, T. M., Deshmukh, M. A (2015) Neuronal stress pathway mediating a histone Methyl/Phospho switch is required for Herpes Simplex Virus Reactivation. Cell Host and Microbe. 18:649-658

Chen, S., Ze, Y., Wilkinson, A., Deshpande, A. J., Krajewski, K., Strahl, B. D., Armstrong, S. A., Patel, D., J. & Gozani, O. (2105) The PZP domain of AF10 senses unmodified H3K27 to regulate DOT1L-mediated methylation of H3K79. Molecular Cell. 60:319-327.

Shanle, E. K, Andrews, F. H., Meriesh, H., McDaniel, S. L., Dronamraiu, R., DiFiore J., Jha, D., Wozniak, G. G., Bridgers, J., Kerschner, J. L., Martin, G. M., Morrison A. J., Krajewski, K., Kutateladze, T*. & Strahl, B. D.* (2015) Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response. Genes & Development. 29:1789-1794.

Simon, J. M., Parker, J. S., Liu, F., Rothbart, S. B., Ait-Si-Ali, S., Strahl, B. D., Jin, j., Davis, I. J., Mosley, A. L. & Pattenden, P. G. (2015) A role for Widely Interspaced Zinc finger (WIZ) in retention of the G9a methyltransferase on chromatin. Journal of Biological Chemistry. 290:26088-26102.

Zhang, Z.-M., Rothbart, S. B., Allison, D., Cai, Q., Harrison, J. S., Li, L., Wang, Y., Strahl B. D., Wang, G. G., Song, J. (2015) An allosteric interaction links USP7 to deubiquitination and chromatin targeting of UHRF1. Cell Reports. 12:1400-1406.

Ali, F. A., Daze, K. D., Rothbart, S. B., Strongin, D. E., Rincon-Arano, H., Allen, H. F., Li, J., Groudine, M., Strahl, B. D., Hof, F. & Kutateladze, T. G. (2015) Calixarenes selectively inhibit binding of the PHD fingers to histone H3K4me3. Journal of Biological Chemistry. 290:22919-22930.

Rothbart, S. B., Dickson, B. M., Raab, J. R., Grzybowski, A. T., Krajewski, K., Guo, A. H., Shanle, E. K., Josefowicz, S. Z., Fuchs, S. M., Allis, C. D., Magnuson, T. R., Ruthenburg, A. J. & Strahl, B. D. (2015) An interactive database for the assessment of histone antibody specificity. Molecular Cell. 59:502-511.

Wang, L., Xie, L., Ramachandran, S., Lee, Y., Yan, Z., Zhou, L., Krajewski, K., Liu, F., Zhu, C., Chen, D., Strahl, B. D., Jin, J., Dokholyan, N. V. & Chen, X. (2015) Non-canonical bromodomain within DNA-PKcs promotes DNA damage response and radioresistance through recognizing an IR-induced acetyl-lysine on H2AX. Chemistry & Biology. 22:1-13.

Rothbart, S. B.*, Dickson, B. M. & Strahl, B. D.* (2015) From Histones to Ribosomes: A Chromatin Regulator Tangoes with Translation. In Press at Cancer Discovery. 5:228-230.

Perfetti, M. T., Baughman, B. M., Dickson, B. D. Mu, Y., Cui, G., Mader, P., Dong, A., Norris, J. L., Rothbart, S. B., Strahl, B. D., Brown, P. J., Janzen, W. P., Arrowsmith, C. H., Mer, G., McBride, K., James, L., & Frye, S. V. (2015) Identification of a Fragment-like Small Molecule Ligand for the Methyl-lysine Binding Protein, 53BP1. ACS Chemical Biology. 10:1072-1081.

McKay, D. J., Klusza, S., Penke, T. J., R., Meers, M. P., Curry, K. P., McDaniel, S. L., Malek, P. Y., Cooper, S. W., Tatomer, D., C., Lieb, J. D., Strahl, B. D., Duronio, R. J. & Matera, A. G. (2015) Interrogating the function of metazoan histones using engineered gene clusters. Developmental Cell. 32:373-86.

Tong, Q., Mazur, S., J., Rincon-Arona, H., Rothbart, S. B., Kuznetsov, D. M., Cui, G., Liu, W. H., Gete, Y., Klein, B. J., Jenkins, L., Mer, G., Kutatelasze, A., G., Strahl, B. D., Groudine, M., G., Appella, E. & Kutateladze, T., G. (2015) An acetyl-methyl switch drives a conformational change in p53. Structure. 23:322-31.

Tong, Q., Cui, G., Botuyan, M. V., Rothbart, S. B., Hayashi, R., Musselman, C. A., Appella, E., Strahl, B. D., Mer, G. & Kutateladze, T. G. (2015) Structural plasticity of methyllysine recognition by the tandem Tudor domain of 53BP1. Structure. 23:312-21.

Dumesic, P. A., Homer, C. M., Moresco, J. J., Pack, L. R., Shanle, E. K., Coyle, S. M., Strahl, B. D., Fujimori, D. G., Yates, J. R. & Madhani, H. D. (2015) Product binding enforces the genomic specificity of a yeast polycomb repressive complex. Cell. 160:1-15.

2014

Gilbert, T. M.*, McDaniel, S. L.*, Byrum., S. D., Cades, J. A., Dancy, B. C. Y, Wade, H., Tackett, A. J., Strahl, B. D.* & Taverna, S. D.* (2014) A PWWP domain-containing protein targets the NuA3 acetyltransferase complex via H3 lysine 36 trimethylation to coordinate transcriptional elongation at coding regions. Mol Cell Proteomics. 13:2883-2895.

Jha, D. K. & Strahl, B. D. (2014) SET-ing the stage for DNA repair. Nat Struct Mol Biol. 5:655-657.

Wozniak, G. G. & Strahl, B. D. (2014) Catalysis-dependent stabilization of Bre1 fine-tunes histone H2B ubiquitylation to regulate gene transcription. Genes & Development. 28:1647-1652.

Shanle, E. K., Rothbart, S. B. & Strahl, B. D. (2014) Chromatin biochemistry enters the next generation of code ‘seq-ing’ Nature Methods. 11:799-800.

Jha, D. K. & Strahl, B. D. (2014) H3K36 methylation regulates chromatin remodeling and checkpoint activation after DSB. Nature Commun. 5:3965.

Greer, E. L., Beese-Sims, S. E., Spadafora, R., Rothbart, S. B., Badeaux, A. I., Strahl, B. D., Colaiácovo, M. P. & Shi, Y. A (2014) histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Reports. 7:113-26.

Wozniak, G. G. & Strahl, B. D. (2014) Hitting the 'Mark': Interpreting Lysine Methylation in the Context of Active Transcription. BBA - Gene Regulatory Mechanisms. 10.1016/j.bbagrm.2014.03.002.

Rothbart S. B. & Strahl, B.D. (2014) Interpreting the language of histone and DNA modifications. BBA - Gene Regulatory Mechanisms. 10.1016/j.bbagrm.2014.03.001

Kim, H.-S., Mukhopadhyay, R., Rothbart, S. B., Silva, A. C., Vanoosthuyse, V., Radovani, E., Kislinger, T., Roguev, A., Ryan, C. J., Xu, J., Jahari, H., Hardwick, K., G., Greenblatt, J. F., Krogan, N. J., Fillingham, J., S., Strahl, B. D., Bouhassira, E., E., Edelmann, W. & Keogh, M.-C. (2014) Identification of a novel Bromodomain/Casein Kinase II/TAF-containing complex as a regulator of mitotic condensin function. Cell Reports. 6:1-14.

Klein, B. J., Piao, L., Xi, Yuanxin, Rincon-Arano, H., ROthbart, S. B., Larson, C., Wen, H., Zheng, X., Cortazar, M., Pena, P. V., Mangan, A., Bentley, D. L., Strahl, B. D., Groudine, M., Li, W., Shi, X., Kutateladze, T. G. (2014) The histone-H3K4-specific demethylase KDM5B binds to its substrate and product through distinct PHD dingers. Cell Reports. 6:1-11.

Dronamraju, R. & Strahl, B. D. (2014) A feed forward circuit comprising Spt6, Ctk1 and PAF regulates Pol II CTD phosphorylation and transcription elongation. Nucleic Acids Research. 42:870-881.



Lab Contact: 

Lab Rooms: 3049G Genetic Medicine
Lab Phone: 919-843-3935
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