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Research Interests
Regulation of gene expression by chromatin structure and dynamics, modulation of chromatin structure by covalent modifications and non-histone chromosomal proteins
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Research Description
Transcription is the process in which the genetic blueprint (DNA) is manifested. All cells in the body contain the same genetic information; how the cell uses this information determines its type and function. These cells must also adapt to a variety of metabolic and environmental signals and do so by altering the patterns of genes expressed, when this regulation goes awry diseases such as cancers develop. Thus, deciphering the mechanisms that regulate gene expression is critical not only for understanding normal cellular functions but also for understanding many diseases.
This regulation does not occur on naked DNA but rather in the context of chromatin. Chromatin is the basic packaging unit for all DNA in the eucaryotic nucleus and represents a formidable barrier to transcription. The cell has evolved not to overcome this repression but rather to use it as a means of regulation. Indeed, numerous regulatory factors have been identified that function by modulating chromatin structure. It is my goal to understand what features of chromatin structure contribute to the regulation of a gene and what factors contribute to the dynamic character of the chromatin fiber.
PCAF (p300/CBP Associated Factor) is a transcriptional coactivator that contains intrinsic histone acetyltransferase (HAT) activity. HATs are positive regulators that promote decompaction of the chromatin fiber by covalently modifying chromatin. In vivo, PCAF exists as part of a multi-protein nuclear complex containing numerous polypeptides. I have compared and found differences in the enzymatic properties of PCAF either alone or as part of the complex. I am studying the architecture and functional contribution of components within the complex under varied in vivo conditions.
A more recent effort involves the study of gene regulation by nuclear receptors. Many nuclear receptors function in part by the recruitment of factors that modify chromatin of the target genes. I have begun to examine the contribution of chromatin structure and the factors involved in the regulation by hepatic nuclear factor 4 (HNF4), a receptor that plays a role in the progression of MODY1 type 2 diabetes. I am focusing on the role of chromatin in this signaling pathway.
Accomplishments
1995-2000
Intramural Research Training Award (IRTA) fellowship
1999
NIH Fellows Award For Research Excellence (FARE)
2000
Invited Speaker at International Workshop; " The Role of HMG proteins in chromatin structure, gene expression and neoplasia" held May 1-2, 2000 at NIH
Recent Publications
Prymakowska-Bosak, M., Herrera, J.E., Hock, R., Garfield, S., and Bustin, M. (2001). Phosphorylation of HMG-14/17 during mitosis. Mol. Cell. Biol., 21:5169-5178 (cover of MCB).
Shirakawa, H., Herrera, J.E., Bustin, M., and Postnikov, Y. (2000). Targeting of high mobility group-14/-17 proteins in chromatin is independent of DNA sequence. J. Biol. Chem. 275, 37937-44.
Herrera, JE, RL Schiltz and M Bustin. (2000) The accessibility of the histone H3 tails in chromatin modulates their acetylation by PCAF. J. Biol. Chem. 275: 12994-99.
Bergel, M, JE Herrera, BJ Thatcher, M Prymakowska-Bosak, A Vassilev, Y Nakatani, B Martin and M Bustin. (2000) Acetylation of novel sites in the nucleosome binding domain of chromosomal protein HMG-14 by p300 alters its interaction with nucleosomes. J. Biol. Chem. 275: 11514-20.
Herrera, JE , KL West, RL Schiltz, Y Nakatani and M Bustin. (2000) Histone H1 is a specific repressor of core histone acetylation in chromatin. Mol. Cell. Biol. 20: 523-529.
Herrera, JE, K Sakaguchi, M Bergel, L Treichman, Y Nakatani and M Bustin. (1999) Specific acetylation of chromosomal protein HMG-17 by PCAF alters its interaction with nucleosomes. Mol. Cell. Biol. 19: 3466-3473.
Sakaguchi, K., Herrera, J.E., Saito, S., Miki, T., Bustin, M., Vassilev, A., Anderson, C.W., and Apella, E., (1998). DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes & Dev. 12: 2831-2841.
Herrera, J.E., Bergel, M., Yang, X-J., Nakatani, Y. and Bustin, M. (1997). The histone acetyltransferase activity of human GCN5 and PCAF is stabilized by coenzymes . J. Biol. Chem. 272, 27253-27258.
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