Woojin An Assistant Professor Biochemistry & Molecular Biology, Norris Comprehensive Cancer Center Keck School of Medicine

Education:
PhD 1998 Biochemistry - Oregon State University, Corvallis, Oregon

Postdoctoral Research Fellowship:
1998-2004 The Rockefeller University

Started at USC: 2004

Research Topics: Gene Regulation/Transcription, Cancer Cell Biology, Signal Transduction, Protein Chemistry/Enzymology, Epigenetics

Research Description

The organization of nuclear DNA within chromatin structure serves not only to compact DNA, but also to regulate its transcription. The histone remodeling activities, which are often targeted to promoter by DNA-bound regulatory factors, result in covalent post-translational modifications (e.g. acetylation, methylation, phosphorylation, ubiquitylation) of core histones. These structurally distinct motifs of modified histones are thought to function as a mark to regulate transcription by recruiting various regulatory factors to specific promoters. To better understand this signaling process, we have established assay systems which utilize recombinant chromatin template and RNAi-complemented ChIP technique. In the case of a cofactor p300-mediated transcription in the context of HeLa nuclear extract, our earlier studies demonstrated selective requirements for histone H3 and H4 N-termini (often called "tails") as well as corresponding promoter-targeted acetylation events. More recently, we also identified indispensable role of multiple/sequential histone modifications in regulating p53-signaling pathway, thus defining combinatorial cofactor functions as well as underlying mechanisms for a p53 target gene regulation.

Albeit these studies have revealed distinct sets of histone modifications in tumor suppressive pathway, it remains unclear how a site-specific histone modification endows p53 with ability to selectively regulate specific target genes. Interestingly, we failed to recapitulate transcriptional activity from chromatin template by using completely purified transcription system, indicating that novel anti-repressive activities are recruited from our nuclear extract; these activities should have an ability to recognize/associate modified histone tails for their recruitment and function. Thus, we currently attempt to purify the (modified) histone tail-recognizing factors, as well as other interacting factors from human cells. Purified factors then will be subjected to mechanistic studies in a well-defined functional assay to establish essential histone marks for p53 function. We are also motivated to investigate the role of histone H2A variants (H2A-Bbd, macroH2A, H2A.Z, H2A.X) in regulation of post-translational chromatin remodeling and transcription. As an initial assessment, we began to determine the properties of histone variants to modulate chromatin structure and transcription using recombinant chromatin template. Once the effect of the histone variants are established, the stage would be set to purify and define the variant-associated activities to identify an underlying mechanism.

Recent studies proposed that site-specific p53 modifications of acetylation, methylation and phosphorylation function as a positive regulator of p53-mediated processes by facilitating the efficient recruitment of transcriptional cofactors to tumor suppressor genes. On this basis, we also challenge to demonstrate that acetylated/methylated lysines and phosphorylated serines of p53 protein function as an epigenetic mark through its recognition/recruitment of cofactor complexes for histone remodeling, thereby allowing promoter access for the core transcription machinery to accomplish stress-induced target gene activation. As a first step, we currently try to define histone modifying activities which are selectively regulated via p53 modification. A logical next step will be to elucidate mechanism of action of p53 modification in well-established functional/structural analysis.

Selected Publications

Heo K, Kim H, Choi SH, Choi J, Kim K, Gu J, Lieber MR, Yang AS, An W. - FACT-Mediated Exchange of Histone Variant H2AX Regulated by Phosphorylation of H2AX and ADP-Ribosylation of Spt16. - Mol Cell [ 2008 ] Apr 11;30(1):86-97 . PubMed

Kim K, Choi J, Heo K, Kim H, Levens D, Kohno K, Johnson EM, Brock HW, An W. - Isolation and Characterization of a Novel H1.2 Complex That Acts as a Repressor of p53-mediated Transcription. - J Biol Chem [ 2008 ] Apr 4;283(14):9113-26 . PubMed

Choi J, Kim B, Heo K, Kim K, Kim H, Zhan Y, Ranish JA, An W. - Purification and characterization of cellular proteins associated with histone H4 tails. - J Biol Chem [ 2007 ] Jul 20;282(29):21024-31 . PubMed

An W. - Histone acetylation and methylation: combinatorial players for transcriptional regulation. - Subcell Biochem [ 2007 ] 41:351-69 . PubMed

Heo K, Kim B, Kim K, Choi J, Kim H, Zhan Y, Ranish JA, An W. - Isolation and characterization of proteins associated with histone H3 tails in vivo. - J Biol Chem [ 2007 ] May 25;282(21):15476-83 . PubMed

Doyen CM, An W, Angelov D, Bondarenko V, Mietton F, Studitsky VM, Hamiche A, Roeder RG, Bouvet P, Dimitrov S. - Mechanism of polymerase II transcription repression by the histone variant macroH2A. - Mol Cell Biol [ 2006 ] Feb;26(3):1156-64 . PubMed

Angelov D, Verdel A, An W, Bondarenko V, Hans F, Doyen CM, Studitsky VM, Hamiche A, Roeder RG, Bouvet P, Dimitrov S. - SWI/SNF remodeling and p300-dependent transcription of histone variant H2ABbd nucleosomal arrays. - EMBO J [ 2004 ] Oct 1;23(19):3815-24 . PubMed

An W, Kim J, Roeder RG. - Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53. - Cell [ 2004 ] Jun 11;117(6):735-48 . PubMed

Thompson PR, Wang D, Wang L, Fulco M, Pediconi N, Zhang D, An W, Ge Q, Roeder RG, Wong J, Levrero M, Sartorelli V, Cotter RJ, Cole PA. - Regulation of the p300 HAT domain via a novel activation loop. - Nat Struct Mol Biol [ 2004 ] Apr;11(4):308-15 . PubMed

An W, Roeder RG. - Reconstitution and transcriptional analysis of chromatin in vitro. - Methods Enzymol [ 2004 ] 377:460-74 . PubMed