Our long-term goal is to understand how misregulation of gene expression leads to oncogenesis, and to learn how to repair transcriptional defects. We have been studying the mechanisms of chromatin modifications and control of transcriptional elongation in the yeast S. cerevisiae. Myriad modifications of histones are important for proper regulation of gene expression. Important among these histone modifications are methylation of H3 on its 4th and 79th lysines (H3K4 and H3K79), which are associated with transcriptionally active genes. Methylation of these residues requires histone H2B to be monoubiquitinated by the Rad6/Bre1 protein complex, a histone cross-talk pathway that is conserved from yeasts to humans. We identified a complex of proteins associated with Set1 (COMPASS) as the yeast H3K4 methyltransferase. Set1 is the homologue of the human mixed lineage leukemia protein, encoded by the MLL gene that is rearranged in a variety of aggressive acute leukemias. We now know that human MLL protein is also found in a COMPASS-like complex capable of catalyzing the methylation of H3K4. We have developed a robust screen of the yeast proteome to identify the machinery required for proper H3K4 methylation. We propose to build on this foundation to define further the molecular machinery involved in the installation and removal of histone H3K4 and K79 methylations, catalyzed by COMPASS and Dot1, respectively. We also propose to leverage our biochemical, enzymological, and genetical expertise to develop inhibitors of H3K4 and K79 methylases and demethylases. Such inhibitors may be useful as lead compounds for the development of targeted therapeutic agents for the treatment of leukemia.
Our specific aims are:
Aim 1 : Define how monoubiquitination of histone H2B regulates histone methylation by COMPASS and Dot1.
Aim 2 : Define the machinery involved in H3K4 and K79 demethylation.
Aim 3 : Identify small molecule inhibitors of H3K4 methylating and demethylating enzymes. Continuation of our yeast studies promises not only to lead to a better understanding of the diverse functional and physiological significance of H3K4 and K79 methylations, but also to forge a link between the basic biology of histone methylation and the treatment of leukemia caused by chromosomal translocations involving the MLL gene.
| 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 |
| 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 |
| 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 |
| Morgan, Marc A; Shilatifard, Ali (2015) Chromatin signatures of cancer. Genes Dev 29:238-49 |
| 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 |
| 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 57:685-694 |
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