Alteration of chromatin by covalent modification of histone proteins is central to regulation of gene expression. Acetylation, the best-characterized covalent modification of histones, has wide-ranging effects on gene expression. Histone phosphorylation is important for transcriptional activation, condensation of chromosomes during mitosis and meiosis, and regulation of cell division. Roles for histone methylation and monoubiquitination in the regulation of gene expression have recently been revealed. For several years we have been studying the role of the MLL protein in the development of human leukemia. Setl protein of S. cerevisiae is closely related to human MLL. We and others have purified a Setl containing multiprotein complex that we call COMPASS. We have demonstrated that COMPASS is required for methylation of lysine 4 in the amino-terminal tail of histone H3, and that this histone modification is required for silencing of expression of genes located near chromosome telomeres. We found that recruitment of COMPASS occurs preferentially at the promoter and with the early elongating polymerase. In a survey of the yeast genome for gene products necessary for histone H3 methylation, we discovered that the ubiquitin-conjugating enzyme Rad6, together with its likely E3 ligase, Bre1, and the Paf1 complex are required for methylation of lysine 4 and lysine 79 of histone H3. Since Rad6 catalyzes monoubiquitination of lysine 123 of histone H2B, this modification of histone H2B may be a signal that directs COMPASS to catalyze methylation of K4 of histone H3. We wish to define the mechanism of histone ubiquitination by Rad6, Brel, and the Pafl complex and their roles in regulation of gene expression via histone modifications by monoubiqutination.
Our specific aims are:
Aim 1 : To understand how monoubiquitination of lysine 123 of histone H2B by Rad6/Bre1 is limited to the promoter regions of genes, and learn about the consequences of this event for gene regulation.
Aim 2 : To learn if monoubiquitination of histone H2B serves as a signal for the recruitment and/or activation of the histone methyltransferase COMPASS.
Aim 3 : To define the molecular mechanism ofdeubiquitination of historic H2B. These studies promise to: i) improve our understanding of the role of histone monoubiquitination in regulation of transcription, ii) shed light on how and why ubiquitination occurs preferentially at promoters, iii) reveal if, why, and how ubiquitination of histones at promoters signals histone methylation, and iv) shed light on the role of the conserved Set domain in yeast Setl and human MLL in development and pathogenesis of hematological malignancies.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069905-02
Application #
6945189
Study Section
Special Emphasis Panel (ZRG1-SSS-U (04))
Program Officer
Carter, Anthony D
Project Start
2004-09-01
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$307,885
Indirect Cost
Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Cao, Kaixiang; Collings, Clayton K; Marshall, Stacy A et al. (2017) SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression. Genes Dev 31:787-801
Cahill 3rd, Thomas J; Thomsen, Alex R B; Tarrasch, Jeffrey T et al. (2017) Distinct conformations of GPCR-?-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A 114:2562-2567
Luo, Zhuojuan; Lin, Chengqi; Woodfin, Ashley R et al. (2016) Regulation of the imprinted Dlk1-Dio3 locus by allele-specific enhancer activity. Genes Dev 30:92-101
De Kumar, Bony; Parrish, Mark E; Slaughter, Brian D et al. (2015) Analysis of dynamic changes in retinoid-induced transcription and epigenetic profiles of murine Hox clusters in ES cells. Genome Res 25:1229-43
Zhang, Pamela; Chaturvedi, Chandra-Prakash; Tremblay, Veronique et al. (2015) A phosphorylation switch on RbBP5 regulates histone H3 Lys4 methylation. Genes Dev 29:123-8
Morgan, Marc A; Shilatifard, Ali (2015) Chromatin signatures of cancer. Genes Dev 29:238-49
Chen, Fei Xavier; Woodfin, Ashley R; Gardini, Alessandro et al. (2015) PAF1, a Molecular Regulator of Promoter-Proximal Pausing by RNA Polymerase II. Cell 162:1003-15
Chen, Fei; Gao, Xin; Shilatifard, Ali (2015) Stably paused genes revealed through inhibition of transcription initiation by the TFIIH inhibitor triptolide. Genes Dev 29:39-47
Zhu, Jiajun; Sammons, Morgan A; Donahue, Greg et al. (2015) Gain-of-function p53 mutants co-opt chromatin pathways to drive cancer growth. Nature 525:206-11
Luo, Zhuojuan; Gao, Xin; Lin, Chengqi et al. (2015) Zic2 is an enhancer-binding factor required for embryonic stem cell specification. Mol Cell 57:685-94

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