Brian D. Strahl

Last updated
Brian David Strahl
Born1970
NationalityAmerican
Known forHistone code hypothesis & Research of histone modifications
Scientific career
FieldsEpigenetics
InstitutionsUniversity of North Carolina at Chapel Hill
Academic advisorsC. David Allis
Website https://www.med.unc.edu/~bstrahl/

Brian David Strahl (born 1970) is an American biochemist and molecular biologist. [1] He is currently a professor in the Department of Biochemistry & Biophysics [2] at the University of North Carolina at Chapel Hill. [3] Strahl is known for his research in the field of chromatin biology and histone modifications. Strahl, with C. David Allis proposed the “histone code hypothesis”. [4]

Contents

Early life and education

Strahl was born in Buffalo, New York and raised in Albuquerque, New Mexico. He moved to Chapel Hill, North Carolina in 1980 when his father went to medical school at the University of North Carolina at Chapel Hill. Strahl entered the University of North Carolina at Greensboro [5] in 1988, where he double majored in Chemistry and Biology. Strahl joined the Department of Biochemistry at North Carolina State University [6] and received his PhD in 1998 under the supervision of Dr. William L. Miller. [7] At North Carolina State University, Strahl defined mechanisms for how the Follicle-Stimulating Hormone-Beta (FSHß) gene is regulated at the transcriptional level. [8] [9] In 1998, Strahl performed postdoctoral studies under the mentorship of Dr. C. David Allis at the University of Virginia’s Department of Biochemistry and Molecular Genetics.

Career

In 2001, Strahl joined the University of North Carolina at Chapel Hill as an assistant professor in the Department of Biochemistry and Biophysics. He was promoted to associate professor in 2008 and full professor in 2014. He also holds an appointment at UNC’s Lineberger Comprehensive Cancer Center [10] and is a faculty member in the Curriculum in Genetics and Molecular Biology. [11] Additionally, Strahl also serves as the faculty director of the UNC High-Throughput Peptide Synthesis and Array Core Facility [12] From 2016 to 2020, he served as the Vice Chair of the Department of Biochemistry & Biophysics at UNC. [13] From 2020 to 2022, he stepped into the role of Interim Chair of Biochemistry and Biophysics. [14] Since 2023, Strahl has held the position of Assistant Dean for Research in the Office of Research at the University of North Carolina School of Medicine. [15] The primary mission of the Office of Research is to develop and implement a strategic plan for research in the School of Medicine(reference). The UNC School of Medicine selected Strahl as an Oliver Smithies Investigator in recognition of his research contributions. [16] This annual award recognizes senior faculty members who have gained international recognition for their work. Since 2015, Strahl has directed UNC's Program on Chromatin and Epigenetics, [17] aiming to understand the complex language of epigenetic regulation. The program seeks to advance human health and address diseases. [18] Stahl is also co-founder of EpiCypher, [19] Inc. [20] – a company known for services for chromatin biology and epigenetics research.

Research and Discoveries

Strahl is a pioneer in the field of epigenetics, with contributions to the study of Chromatin biology. As a postdoctoral fellow in C. David Allis’ laboratory, helped to establish the identity of the first lysine and arginine histone methyltransferases and how they contribute to transcriptional activation and heterochromatin formation. Some examples include the discovery of the first histone methyltransferases that target lysine 4 (Set1), [21] lysine 9 (SUV39H1), [22] and lysine 36 of histone H3 (Set2/SETD2) [23] and arginine 3 of histone H4 (PRMT1). [24] Strahl also helped to develop the first antibodies for methylated histones in the Allis laboratory. In 2000, Strahl and Allis put forward the idea of the “histone code hypothesis”, which aimed to explain how multiple histone modifications function together to control chromatin structure and function. [4] The early years of the Strahl laboratory, research focused on the roles of histone methylation and histone ubiquitylation in gene transcription. He linked histone H2B ubiquitylation to the regulation of H3 lysine 79 methylation and in transcriptional elongation [25] [26] and determined how H3 lysine 36 methylation is coupled to RNA Polymerase II [27] and repressive chromatin during transcription elongation. [28] His group also defined the key roles of several histone chaperones (e.g., Spt6) that function in transcription [29] [30] In more recent years, Strahl turned his attention to how chromatin-associated proteins engage histones and their modifications. Through the development of a peptide microarray platform, [31] his group uncovered mechanisms of DNA methylation maintenance [32] [33] and defined modes of chromatin engagement by distinct families of histone-binding effector domains. [34] [35] [36] Recent work has also turned to how recently defined effector domains, including the YEATS domain, contribute to chromatin function and metabolic transcription [37] [38]

Related Research Articles

<span class="mw-page-title-main">Histone</span> Protein family around which DNA winds to form nucleosomes

In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes. Nucleosomes in turn are wrapped into 30-nanometer fibers that form tightly packed chromatin. Histones prevent DNA from becoming tangled and protect it from DNA damage. In addition, histones play important roles in gene regulation and DNA replication. Without histones, unwound DNA in chromosomes would be very long. For example, each human cell has about 1.8 meters of DNA if completely stretched out; however, when wound about histones, this length is reduced to about 90 micrometers (0.09 mm) of 30 nm diameter chromatin fibers.

Histone methylation is a process by which methyl groups are transferred to amino acids of histone proteins that make up nucleosomes, which the DNA double helix wraps around to form chromosomes. Methylation of histones can either increase or decrease transcription of genes, depending on which amino acids in the histones are methylated, and how many methyl groups are attached. Methylation events that weaken chemical attractions between histone tails and DNA increase transcription because they enable the DNA to uncoil from nucleosomes so that transcription factor proteins and RNA polymerase can access the DNA. This process is critical for the regulation of gene expression that allows different cells to express different genes.

<span class="mw-page-title-main">Charles David Allis</span> American molecular biologist (1951–2023)

Charles David Allis was an American molecular biologist, and the Joy and Jack Fishman Professor at the Rockefeller University. He was also the Head of the Laboratory of Chromatin Biology and Epigenetics, and a professor at the Tri-Institutional MD–PhD Program.

The histone code is a hypothesis that the transcription of genetic information encoded in DNA is in part regulated by chemical modifications to histone proteins, primarily on their unstructured ends. Together with similar modifications such as DNA methylation it is part of the epigenetic code. Histones associate with DNA to form nucleosomes, which themselves bundle to form chromatin fibers, which in turn make up the more familiar chromosome. Histones are globular proteins with a flexible N-terminus that protrudes from the nucleosome. Many of the histone tail modifications correlate very well to chromatin structure and both histone modification state and chromatin structure correlate well to gene expression levels. The critical concept of the histone code hypothesis is that the histone modifications serve to recruit other proteins by specific recognition of the modified histone via protein domains specialized for such purposes, rather than through simply stabilizing or destabilizing the interaction between histone and the underlying DNA. These recruited proteins then act to alter chromatin structure actively or to promote transcription. For details of gene expression regulation by histone modifications see table below.

<span class="mw-page-title-main">Histone-modifying enzymes</span> Type of enzymes

Histone-modifying enzymes are enzymes involved in the modification of histone substrates after protein translation and affect cellular processes including gene expression. To safely store the eukaryotic genome, DNA is wrapped around four core histone proteins, which then join to form nucleosomes. These nucleosomes further fold together into highly condensed chromatin, which renders the organism's genetic material far less accessible to the factors required for gene transcription, DNA replication, recombination and repair. Subsequently, eukaryotic organisms have developed intricate mechanisms to overcome this repressive barrier imposed by the chromatin through histone modification, a type of post-translational modification which typically involves covalently attaching certain groups to histone residues. Once added to the histone, these groups elicit either a loose and open histone conformation, euchromatin, or a tight and closed histone conformation, heterochromatin. Euchromatin marks active transcription and gene expression, as the light packing of histones in this way allows entry for proteins involved in the transcription process. As such, the tightly packed heterochromatin marks the absence of current gene expression.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

H3K4me3 is an epigenetic modification to the DNA packaging protein Histone H3 that indicates tri-methylation at the 4th lysine residue of the histone H3 protein and is often involved in the regulation of gene expression. The name denotes the addition of three methyl groups (trimethylation) to the lysine 4 on the histone H3 protein.

H3K27me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation of lysine 27 on histone H3 protein.

<span class="mw-page-title-main">Thomas Jenuwein</span> German scientist

Thomas Jenuwein is a German scientist working in the fields of epigenetics, chromatin biology, gene regulation and genome function.

H3K9me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 9th lysine residue of the histone H3 protein and is often associated with heterochromatin.

H3K9me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 9th lysine residue of the histone H3 protein. H3K9me2 is strongly associated with transcriptional repression. H3K9me2 levels are higher at silent compared to active genes in a 10kb region surrounding the transcriptional start site. H3K9me2 represses gene expression both passively, by prohibiting acetylation as therefore binding of RNA polymerase or its regulatory factors, and actively, by recruiting transcriptional repressors. H3K9me2 has also been found in megabase blocks, termed Large Organised Chromatin K9 domains (LOCKS), which are primarily located within gene-sparse regions but also encompass genic and intergenic intervals. Its synthesis is catalyzed by G9a, G9a-like protein, and PRDM2. H3K9me2 can be removed by a wide range of histone lysine demethylases (KDMs) including KDM1, KDM3, KDM4 and KDM7 family members. H3K9me2 is important for various biological processes including cell lineage commitment, the reprogramming of somatic cells to induced pluripotent stem cells, regulation of the inflammatory response, and addiction to drug use.

<span class="mw-page-title-main">Yi Zhang (biochemist)</span> Chinese-American biochemist

Yi Zhang is a Chinese-American biochemist who specializes in the fields of epigenetics, chromatin, and developmental reprogramming. He is a Fred Rosen Professor of Pediatrics and professor of genetics at Harvard Medical School, a senior investigator of Program in Cellular and Molecular Medicine at Boston Children's Hospital, and an investigator of the Howard Hughes Medical Institute. He is also an associate member of the Harvard Stem Cell Institute, as well as the Broad Institute of MIT and Harvard. He is best known for his discovery of several classes of epigenetic enzymes and the identification of epigenetic barriers of SCNT cloning.

H3K4me1 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the mono-methylation at the 4th lysine residue of the histone H3 protein and often associated with gene enhancers.

H3K36me3 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the tri-methylation at the 36th lysine residue of the histone H3 protein and often associated with gene bodies.

H3K79me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 79th lysine residue of the histone H3 protein. H3K79me2 is detected in the transcribed regions of active genes.

H4K20me is an epigenetic modification to the DNA packaging protein Histone H4. It is a mark that indicates the mono-methylation at the 20th lysine residue of the histone H4 protein. This mark can be di- and tri-methylated. It is critical for genome integrity including DNA damage repair, DNA replication and chromatin compaction.

H3K14ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 14th lysine residue of the histone H3 protein.

H3K36ac is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the acetylation at the 36th lysine residue of the histone H3 protein.

H3K36me2 is an epigenetic modification to the DNA packaging protein Histone H3. It is a mark that indicates the di-methylation at the 36th lysine residue of the histone H3 protein.

H3K36me is an epigenetic modification to the DNA packaging protein Histone H3, specifically, the mono-methylation at the 36th lysine residue of the histone H3 protein.

References

  1. ↑ "Brian D. Strahl". Biochemistry and Biophysics.
  2. ↑ "UNC Department of Biochemistry and Biophysics". Biochemistry and Biophysics.
  3. ↑ "The University of North Carolina at Chapel Hill". The University of North Carolina at Chapel Hill. March 27, 2024.
  4. 1 2 Strahl, Brian D.; Allis, C. David (January 26, 2000). "The language of covalent histone modifications". Nature. 403 (6765): 41–45. Bibcode:2000Natur.403...41S. doi:10.1038/47412. PMID   10638745 – via www.nature.com.
  5. ↑ "Home Page". UNC Greensboro.
  6. ↑ "North Carolina State University". NC State University.
  7. ↑ "William Miller". Molecular and Structural Biochemistry.
  8. ↑ https://academic.oup.com/endo/article/139/11/4455/2986812?login=true
  9. ↑ https://academic.oup.com/endo/article/138/6/2621/2987988
  10. ↑ "Brian D. Strahl". UNC Lineberger.
  11. ↑ "GMB Faculty | Curriculum in Genetics and Molecular Biology". gmb.unc.edu.
  12. ↑ "Contact | UNC High-Throughput Peptide Synthesis and Array Facility". www.med.unc.edu.
  13. ↑ "Epigenetics: Brian Strahl, Ph.D., Faculty Spotlight". October 2018.
  14. ↑ "Strahl named Interim Chair, Department of Biochemistry and Biophysics". 9 April 2020.
  15. ↑ "Strahl Named Interim Assistant Dean for Research". School of Medicine Intranet. June 7, 2023.
  16. ↑ Clabo, Carolyn (January 31, 2018). "Strahl named Smithies Investigator". Biochemistry and Biophysics.
  17. ↑ "Faculty | Chromatin and Epigenetics Program". www.med.unc.edu.
  18. ↑ "Chromatin and Epigenetics Program". www.med.unc.edu.
  19. ↑ "EpiCypher Scientific Founders". www.epicypher.com.
  20. ↑ "EpiCypher | Bringing Epigenetics to Life | For scientists. By scientists". www.epicypher.com.
  21. ↑ Briggs, S. D.; Bryk, M.; Strahl, B. D.; Cheung, W. L.; Davie, J. K.; Dent, S. Y.; Winston, F.; Allis, C. D. (2001). "Histone H3 lysine 4 methylation is mediated by Set1 and required for cell growth and rDNA silencing in Saccharomyces cerevisiae". Genes & Development. 15 (24): 3286–3295. doi:10.1101/gad.940201. PMC   312847 . PMID   11751634.
  22. ↑ Rea, S.; Eisenhaber, F.; O'Carroll, D.; Strahl, B. D.; Sun, Z. W.; Schmid, M.; Opravil, S.; Mechtler, K.; Ponting, C. P.; Allis, C. D.; Jenuwein, T. (2000). "Regulation of chromatin structure by site-specific histone H3 methyltransferases". Nature. 406 (6796): 593–599. doi:10.1038/35020506. PMID   10949293.
  23. ↑ Strahl, B. D.; Grant, P. A.; Briggs, S. D.; Sun, Z. W.; Bone, J. R.; Caldwell, J. A.; Mollah, S.; Cook, R. G.; Shabanowitz, J.; Hunt, D. F.; Allis, C. D. (2002). "Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression". Molecular and Cellular Biology. 22 (5): 1298–1506. doi:10.1128/MCB.22.5.1298-1306.2002. PMC   134702 . PMID   11839797.
  24. ↑ Strahl, B. D.; Briggs, S. D.; Brame, C. J.; Caldwell, J. A.; Koh, S. S.; Ma, H.; Cook, R. G.; Shabanowitz, J.; Hunt, D. F.; Stallcup, M. R.; Allis, C. D. (2001). "Methylation of histone H4 at arginine 3 occurs in vivo and is mediated by the nuclear receptor coactivator PRMT1". Current Biology. 11 (12): 996–1000. Bibcode:2001CBio...11..996S. doi: 10.1016/s0960-9822(01)00294-9 . PMID   11448779.
  25. ↑ Briggs, Scott D.; Xiao, Tiaojiang; Sun, Zu-Wen; Caldwell, Jennifer A.; Shabanowitz, Jeffrey; Hunt, Donald F.; Allis, C. David; Strahl, Brian D. (August 26, 2002). "Trans-histone regulatory pathway in chromatin". Nature. 418 (6897): 498. doi:10.1038/nature00970. PMID   12152067 – via www.nature.com.
  26. ↑ Xiao, T.; Kao, C. F.; Krogan, N. J.; Sun, Z. W.; Greenblatt, J. F.; Osley, M. A.; Strahl, B. D. (2005). "Histone H2B ubiquitylation is associated with elongating RNA polymerase II". Molecular and Cellular Biology. 25 (2): 637–651. doi:10.1128/MCB.25.2.637-651.2005. PMC   543430 . PMID   15632065.
  27. ↑ Xiao, T.; Hall, H.; Kizer, K. O.; Shibata, Y.; Hall, M. C.; Borchers, C. H.; Strahl, B. D. (2003). "Phosphorylation of RNA polymerase II CTD regulates H3 methylation in yeast". Genes & Development. 17 (5): 654–663. doi:10.1101/gad.1055503. PMC   196010 . PMID   12629047.
  28. ↑ Keogh, M. C.; Kurdistani, S. K.; Morris, S. A.; Ahn, S. H.; Podolny, V.; Collins, S. R.; Schuldiner, M.; Chin, K.; Punna, T.; Thompson, N. J.; Boone, C.; Emili, A.; Weissman, J. S.; Hughes, T. R.; Strahl, B. D.; Grunstein, M.; Greenblatt, J. F.; Buratowski, S.; Krogan, N. J. (2005). "Cotranscriptional Set2 Methylation of Histone H3 Lysine 36 Recruits a Repressive Rpd3 Complex - ScienceDirect". Cell. 123 (4): 593–605. doi:10.1016/j.cell.2005.10.025. PMID   16286008.
  29. ↑ 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 (2): 870–881. doi:10.1093/nar/gkt1003. PMC   3902893 . PMID   24163256.
  30. ↑ "Spt6 Association with RNA Polymerase II Directs mRNA Turnover During Transcription - ScienceDirect". doi:10.1016/j.molcel.2018.05.020. PMID   29932900.
  31. ↑ Rothbart, S. B.; Krajewski, K.; Strahl, B. D.; Fuchs, S. M. (2012). "Peptide Microarrays to Interrogate the "Histone Code"". Nucleosomes, Histones & Chromatin Part A. Methods in Enzymology. Vol. 512. pp. 107–135. doi:10.1016/B978-0-12-391940-3.00006-8. ISBN   978-0-12-391940-3. PMC   3741997 . PMID   22910205.
  32. ↑ Rothbart, S. B.; Krajewski, K.; Nady, N.; Tempel, W.; Xue, S.; Badeaux, A. I.; Barsyte-Lovejoy, D.; Martinez, J. Y.; Bedford, M. T.; Fuchs, S. M.; Arrowsmith, C. H.; Strahl, B. D. (2012). "Association of UHRF1 with methylated H3K9 directs the maintenance of DNA methylation". Nature Structural & Molecular Biology. 19 (11): 1155–1160. doi:10.1038/nsmb.2391. PMC   3492551 . PMID   23022729.
  33. ↑ Rothbart, S. B.; Dickson, B. M.; Ong, M. S.; Krajewski, K.; Houliston, S.; Kireev, D. B.; Arrowsmith, C. H.; Strahl, B. D. (2013). "Multivalent histone engagement by the linked tandem Tudor and PhD domains of UHRF1 is required for the epigenetic inheritance of DNA methylation". Genes & Development. 27 (11): 1288–1298. doi:10.1101/gad.220467.113. PMC   3690401 . PMID   23752590.
  34. ↑ Shanle, E. K.; Shinsky, S. A.; Bridgers, J. B.; Bae, N.; Sagum, C.; Krajewski, K.; Rothbart, S. B.; Bedford, M. T.; Strahl, B. D. (2017). "Histone peptide microarray screen of chromo and Tudor domains defines new histone lysine methylation interactions". Epigenetics & Chromatin. 10: 12. doi: 10.1186/s13072-017-0117-5 . PMC   5348760 . PMID   28293301.
  35. ↑ Jain, K.; Fraser, C. S.; Marunde, M. R.; Parker, M. M.; Sagum, C.; Burg, J. M.; Hall, N.; Popova, I. K.; Rodriguez, K. L.; Vaidya, A.; Krajewski, K.; Keogh, M. C.; Bedford, M. T.; Strahl, B. D. (2020). "Characterization of the plant homeodomain (PHD) reader family for their histone tail interactions". Epigenetics & Chromatin. 13 (1): 3. doi: 10.1186/s13072-020-0328-z . PMC   6979384 . PMID   31980037.
  36. ↑ Jain, K.; Marunde, M. R.; Burg, J. M.; Gloor, S. L.; Joseph, F. M.; Poncha, K. F.; Gillespie, Z. B.; Rodriguez, K. L.; Popova, I. K.; Hall, N. W.; Vaidya, A.; Howard, S. A.; Taylor, H. F.; Mukhsinova, L.; Onuoha, U. C.; Patteson, E. F.; Cooke, S. W.; Taylor, B. C.; Weinzapfel, E. N.; Cheek, M. A.; Meiners, M. J.; Fox, G. C.; Namitz KEW; Cowles, M. W.; Krajewski, K.; Sun, Z. W.; Cosgrove, M. S.; Young, N. L.; Keogh, M. C.; Strahl, B. D. (2023). "An acetylation-mediated chromatin switch governs H3K4 methylation read-write capability". eLife. 12. doi: 10.7554/eLife.82596 . PMC   10229121 . PMID   37204295.
  37. ↑ "Recognition of Histone Crotonylation by Taf14 Links Metabolic State to Gene Expression - ScienceDirect". doi:10.1016/j.molcel.2019.09.029.
  38. ↑ Zhang, J.; Gundu, A.; Strahl, B. D. (2021). "Recognition of acetylated histone by Yaf9 regulates metabolic cycling of transcription initiation and chromatin regulatory factors". Genes & Development. 35 (23–24): 1678–1692. doi:10.1101/gad.348904.121. PMC   8653784 . PMID   34819351.
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