Brian Strahl, PhD

RESEARCH INTERESTS:

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. Thus, a significant question to ask is how chromatin environments are established and maintained, as well as made permissive to the machineries that drive transcription, replication, recombination, and repair. One mechanism known to regulate chromatin structure and function involves histone post-translational modifications. Various modifications, such as acetylation and methylation, exist on histones and studies indicate that they work together in the form of a ‘histone code’ to regulate chromatin-based activities. Recent insights show that histone modifications play a fundamental role in the activation and repression of genes, and in the organization of distinct chromosomal domains. Not surprisingly, many of the enzymes responsible for mediating histone modifications are found to be mis-regulated or translocated in many human diseases, especially cancer.

In our laboratory, we use budding yeast as a model organism to determine the functions of histone modifications, most notably methylation and ubiquitination. We and others have found that a variety of enzymes which either methylate (e.g. Set1 and Set2) or ubiquitinate (e.g. Rad6) histones are associated with RNA polymerase II during the elongation cycle of transcription. While Set2 associates directly with the C-terminal domain of RNA polymerase II, Rad6 and Set1 associate with the polymerase through an interaction with the PAF transcription elongation complex. Recent evidence suggests that these enzymes, via their chromatin modifications, regulate a number of crucial aspects of the transcription process. For example, while Set1-mediated methylation of histone H3 at lysine 4 is associated with nucleosome disruption at the 5' end of genes, Set2-mediated methylation of histone H3 at lysine 36 is associated with nucleosome stability at the 3' end of genes. Current efforts are aimed at understanding how these enzymes contribute to chromatin organization, nucleosome stability and gene regulation.

RECENT PUBLICATIONS:

Fuchs SM, Laribee RN, Strahl BD (2009) Protein modifications in transcription elongation. BBA - Gene Regulatory Mechanisms. 1789:26-36.

Youdell MJ*, Kizer OK*, Kisseleva-Romanova E, Fuchs SM, Duro E, Korn K, Strahl BD, Mellor J (2008) Spt6 controls methylation of lysine 36 on histone H3 to stabilize transcribed chromatin. Mol Cell Biol. 16:4915-4926.

Henikoff S, Strahl BD, Warburton PE (2008) Epigenomics: a roadmap to chromatin. Science. 322:853.

Rivenbark AG, Strahl BD. Molecular biology. Unlocking cell fate. Science. 2007 Oct 19;318(5849):403-4

Wyce A, Xiao T, Whelan KA, Kosman C, Walter W, Eick D, Hughes TR, Krogan NJ, Strahl BD, Berger SL. H2B ubiquitylation acts as a barrier to Ctk1 nucleosomal recruitment prior to removal by Ubp8 within a SAGA-related complex. Mol Cell. 2007 Jul 20;27(2):275-88

Laribee RN, Fuchs SM, Strahl BD. H2B ubiquitylation in transcriptional control: a FACT-finding mission. Genes Dev. 2007 Apr 1;21(7):737-43

Laribee RN, Shibata Y, Mersman DP, Collins SR, Kemmeren P, Roguev A, Weissman JS, Briggs SD, Krogan NJ, Strahl BD. CCR4/NOT complex associates with the proteasome and regulates histone methylation. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5836-41. Epub 2007

Morris SA, Rao B, Garcia BA, Hake SB, Diaz RL, Shabanowitz J, Hunt DF, Allis CD, Lieb JD, Strahl BD. Identification of histone H3 lysine 36 acetylation as a highly conserved histone modification. J Biol Chem. 2007 Mar 9;282(10):7632-40. Epub 2006

Kizer KO, Xiao T, Strahl BD. Accelerated nuclei preparation and methods for analysis of histone modifications in yeast. Methods. 2006 Dec;40(4):296-302

Xiao T, Shibata Y, Rao B, Laribee RN, O'Rourke R, Buck MJ, Greenblatt JF, Krogan NJ, Lieb JD, Strahl BD. The RNA polymerase II kinase Ctk1 regulates positioning of a 5' histone methylation boundary along genes. Mol Cell Biol. 2007 Jan;27(2):721-31. Epub 2006