DNA methylation and histone post-translational modifications (PTMs) elicit influence on chromatin-templated biological processes, and these `epigenetic' marks are often aberrantly regulated in cancers. Elucidation of mechanisms controlling DNA methylation and histone PTMs are therefore important to better our understanding of the role of epigenetics in cancer. The E3 ubiquitin ligase UHRF1 is genetically linked to the maintenance of cellular DNA methylation and deregulation of UHRF1 correlates with cell proliferation, metastasis, and hypersensitivity to DNA damaging agents. These recent connections of UHRF1 to the regulation of DNA methylation and cancer progression suggest this protein may be a favorable therapeutic target. Yet, many fundamental aspects of UHRF1 biology are not known. The overarching goal of this K99/R00 proposal is therefore to advance our understanding of the interaction of UHRF1 with chromatin and the regulation of DNA methylation inheritance. My preliminary studies established that recognition of methylated histone H3 at lysine 9 by the UHRF1 tandem Tudor domain is required for its DNA methylation maintenance function. Studies in this proposal will build upon these findings to: 1) define how multivalent chromatin engagement drives the DNA methylation maintenance function of UHRF1, 2) determine the spatial and temporal contribution of UHRF1 to DNA methylation maintenance, 3) define the UHRF1 interactome, and 4) develop chemical probes as tools to study UHRF1 function. This proposal is supported by a strong mentorship and training plan, building a solid foundation for a successful independent research career investigating the regulation of the epigenetic program and how its dysfunction leads to the initiation and progression of cancer.

Public Health Relevance

A complete copy of the human genome is packaged inside every cell of our body by wrapping around histone proteins. Small chemical `epigenetic' tags on both DNA and histones help regulate the accessibility of the genetic information encoded within our DNA, controlling whether certain genes are switched on or off. The patterning of epigenetic tags in cancer cells is often changed, and increasing evidence suggests these changes may be underlying causes of malignant transformation. By gaining a basic understanding of how epigenetic tags are regulated, this proposal aims to learn new ways in which normal human cells become cancerous and identify new cellular targets for cancer treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Transition Award (R00)
Project #
4R00CA181343-03
Application #
9021937
Study Section
Special Emphasis Panel (NSS)
Program Officer
Okano, Paul
Project Start
2015-04-01
Project End
2018-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
$248,672
Indirect Cost
$85,072
Name
Van Andel Research Institute
Department
Type
DUNS #
129273160
City
Grand Rapids
State
MI
Country
United States
Zip Code
49503
Shah, Rohan N; Grzybowski, Adrian T; Cornett, Evan M et al. (2018) Examining the Roles of H3K4 Methylation States with Systematically Characterized Antibodies. Mol Cell 72:162-177.e7
Veland, Nicolas; Hardikar, Swanand; Zhong, Yi et al. (2017) The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer. Cell Rep 21:3390-3397
Cornett, Evan M; Dickson, Bradley M; Rothbart, Scott B (2017) Analysis of Histone Antibody Specificity with Peptide Microarrays. J Vis Exp :
Shanle, Erin K; Shinsky, Stephen A; Bridgers, Joseph B et al. (2017) Histone peptide microarray screen of chromo and Tudor domains defines new histone lysine methylation interactions. Epigenetics Chromatin 10:12
Ma, Honglei; Duan, Jingbo; Ke, Jiyuan et al. (2017) A D53 repression motif induces oligomerization of TOPLESS corepressors and promotes assembly of a corepressor-nucleosome complex. Sci Adv 3:e1601217
Cornett, E M; Dickson, B M; Vaughan, R M et al. (2016) Substrate Specificity Profiling of Histone-Modifying Enzymes by Peptide Microarray. Methods Enzymol 574:31-52
Busby, Michele; Xue, Catherine; Li, Catherine et al. (2016) Systematic comparison of monoclonal versus polyclonal antibodies for mapping histone modifications by ChIP-seq. Epigenetics Chromatin 9:49
Dickson, B M; Cornett, E M; Ramjan, Z et al. (2016) ArrayNinja: An Open Source Platform for Unified Planning and Analysis of Microarray Experiments. Methods Enzymol 574:53-77
Dickson, Bradley M; de Waal, Parker W; Ramjan, Zachary H et al. (2016) A fast, open source implementation of adaptive biasing potentials uncovers a ligand design strategy for the chromatin regulator BRD4. J Chem Phys 145:154113
Andrews, Forest H; Tong, Qiong; Sullivan, Kelly D et al. (2016) Multivalent Chromatin Engagement and Inter-domain Crosstalk Regulate MORC3 ATPase. Cell Rep 16:3195-3207

Showing the most recent 10 out of 25 publications