Brian D Strahl
Biochemistry & Biophysics
Cancer Cell Biology
Brian Strahl - UNC Departmental website
CV or Biosketch
Area of interest
DNA is faithfully packaged within the nuclei of our cells through the actions of histone proteins. These proteins create individual histone-DNA complexes referred to as nucleosomes, which are further folded into higher-order chromatin structures that are still poorly defined. To a large extent, chromatin structure and function is dictated by histone post-translational modifications, which include acetylation, methylation, ubiquitylation and phosphorylation. Studies indicate that these modifications work together in the form of a 'histone code' to regulate the recruitment of effector proteins that then alter the structure and function of chromatin.
Although chromatin has been studied intensely, we still know very little regarding how distinct chromosomal domains such as "euchromatin" and "heterochromatin" become established and maintained, and how the underlying DNA within this highly compact and repressive environment is made accessible to the protein machineries that need to utilize it. is addressing these issues by examining the process of RNA polymerase II transcription. We aim to understand how gene transcription occurs at the "right place" and at the "right time" in the genome, and the mechanisms by which histones, histone variants, and histone post-translational modifications contribute to this event. Recently, the Strahl lab and others have identified roles for several histone-modifying enzymes during the transcription process. These enzymes associate with the polymerase during transcript elongation and alter the chromatin environment to make it more or less permissive for transcriptional initiation and elongation events. As an example, co-transcriptional methylation of histone H3 at lysine 36 by Set2 results in the recruitment of a histone deacetylase complex that keeps the coding region of genes in a more repressed state that is resistant to inappropriate transcriptional initiation and histone exchange. Current efforts are aimed at understanding how this and other histone-modifying enzymes contribute to chromatin organization, nucleosome stability and gene regulation.
Finally, Brian Strahl's group 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. These exciting projects are helping to bring new insight into how histones, and the modifications they contain, drive fundamentally important biological processes such as gene transcription and DNA repair in cells, and how their mis-regulation leads to human diseases such as cancer.
Awards and Honors
2009 Recipient of the UNC Chapel Hill Ruth and Phillip Hettleman Prize for Artistic and Scholarly Achievement
2008 Recipient of an Exceptional, Unconventional Research Enabling Knowledge Acceleration (EUREKA) award
2006 Named as a Jefferson-Pilot Fellow in Academic Medicine, UNC Chapel Hill
2005 Recipient of the ASBMB Schering-Plough Research Institute Award for outstanding research contributions to biochemistry and molecular biology
2004 Pew Scholar in the Biomedical Sciences
2003 Recipient of a Presidential Early Career Award (PECASE)
Recent Publications (2015 & 2016)
- 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. 160:204-218.
- 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.
- 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. An acetyl-methyl switch drives a conformational change in p53. Structure. 23:322-31.
- 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.
- 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.
- Rothbart, S. B., Dickson, B. M. & Strahl, B. D. (2015) From Histones to Ribosomes: A Chromatin Regulator Tangoes with Translation. Cancer Discovery. 5:228-30.
- 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., 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.
- 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) Molecular Insights into Inhibition of the Methylated Histone-Plant Homeodomain Complexes by Calixarenes. Journal of Biological Chemistry. 290:22919-22930.
- 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.
- 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.
- 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., Martín, 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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 Biology. 12:396-398.
- 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.
- 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.
- 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. 574:3-29.
- 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.
- 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. 30:1866-1880.
- 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. pii: e17101. doi: 10.7554/eLife.17101.
- 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. 291: 21283-21295.
- Andrews, F. H., Tong, Q., Sullivan, K. D., Cornett, E., Zhang, Y., Muzaffar, A., Ahn, J., Strahl, B. D., Costello, J. C., Espinosa, J. M., Rothbart, S., B. & Kutateladze, T. G. (2016) Multivalent chromatin engagement and inter-domain crosstalk regulate MORC3 ATPase. Cell Reports. 16:3195-31207.
- Strikoudis, A., Lazaris, C., Trimarchi, T., Galvao Neto, A. L., Yang, Y., Ntziachristos, P., Rothbart, S. D., Buckley, S., Dolgalev, I., Stadtfeld, M., Strahl, B. D., Dynlacht, B. D., Tsirigos, A & Aifantis, I. Regulation of transcriptional elongation in pluripotency and cell differentiation by the PHD-finger protein Phf5a. Nature Cell Biology. 18:1127-1138.
- Charpentier, T. H., Waldo, G. L., Lowery-Gionta, E. G., Krajewski, K., Strahl, B. D., Kash, T. L., Harden, K. & Sondek, J. (2016) Potent and selective peptide-based inhibition of Gαq. Journal of Biological Chemistry. 18:1127-1138.
- Savitsky, P., Krojer, T., Fujisawa, T., Lambert, J.P., Picaud, S., Wang, C.Y., Shnale, E. K., Krajewski, K., Friedrichsen, H., Kanapin, A., Goding, C., Schapira, M., Samsonova, A., Strahl, B. D., Gingras, A.C. & Filippakopoulos, P. (2016) Multivalent histone and DNA engagement by a PHD/BRD/PWWP triple reader cassette recruits ZMYND8 to K14ac-rich chromatin. Cell Reports. 17:2724-2737.