Epigenetic patterns provide an extra layer of gene regulation beyond the genomic sequence and play a critical role in the maintenance of cell-type specific gene expression programs. Disruption of epigenetic regulation can cause severe diseases including cancer. During the past few years, a large amount of epigenomic data have been generated displaying significant epigenetic pattern changes across cell- types and in disease tissues. On the other hand, the targeting mechanism for epigenetic factors remains poorly understood. The investigators propose integrated computational and experimental approaches to tackle this challenge, summarized by the following three specific aims.
In Aim 1, a wavelet analysis-based computational approach will be developed to predict genome-wide epigenetic patterns using DNA sequence information.
In Aim 2, gene expression data will be further integrated to predict tissue-specific epigenetic changes.
In Aim 3, controlled experiments will be carried out in mouse embryonic stem cells to validate computational predictions. If successful, our proposed research will provide mechanistic insights into epigenetic targeting and can be used to develop tools to reverse specific disease-causing, aberrant epigenetic changes as a potential novel therapeutic approach for cancer and other diseases. Our preliminary studies suggest that a wavelet-based computational approach, previously developed by the principal investigator and colleagues, is effective for the prediction of a number of epigenetic modifications. This approach will be optimized in Aim 1 for de novo detection of sequence features associated with various epigenetic modifications by incorporating more effective wavelet tools such as thresholding and wavelet packet analysis. The strength will be further enhanced by incorporating previously annotated sequence features and by using a more effective classification method.
For Aim 2, gene expression data will be combined with sequence analysis to predict tissue-specific epigenetic changes. A sparse principal component regression method will be used to identify the tissue-specific, context dependent regulatory effects of modules each characterized by a combinatorial pattern of multiple regulators.
For Aim 3, we will select DNA sequences and regulatory modules based on computational predictions and experimentally test their roles in epigenetic targeting by using a number of assays including introducing genetic mutations, forcing or inhibiting gene expression levels, and chromatin immunoprecipitation.

Public Health Relevance

The proposed research will identify key regulatory factors responsible for aberrant epigenetic profiles in cancer and other diseases. It will also help identify novel epigenetic therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Research Project (R01)
Project #
5R01HG005085-03
Application #
8420497
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Pazin, Michael J
Project Start
2011-02-18
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
3
Fiscal Year
2013
Total Cost
$417,813
Indirect Cost
$179,063
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Guo, Guoji; Pinello, Luca; Han, Xiaoping et al. (2016) Serum-Based Culture Conditions Provoke Gene Expression Variability in Mouse Embryonic Stem Cells as Revealed by Single-Cell Analysis. Cell Rep 14:956-65
Jadhav, Unmesh; Nalapareddy, Kodandaramireddy; Saxena, Madhurima et al. (2016) Acquired Tissue-Specific Promoter Bivalency Is a Basis for PRC2 Necessity in Adult Cells. Cell 165:1389-400
Canver, Matthew C; Smith, Elenoe C; Sher, Falak et al. (2015) BCL11A enhancer dissection by Cas9-mediated in situ saturating mutagenesis. Nature 527:192-7
Wu, Jennifer N; Pinello, Luca; Yissachar, Elinor et al. (2015) Functionally distinct patterns of nucleosome remodeling at enhancers in glucocorticoid-treated acute lymphoblastic leukemia. Epigenetics Chromatin 8:53
Wu, Gengze; Cai, Jin; Han, Yu et al. (2014) LincRNA-p21 regulates neointima formation, vascular smooth muscle cell proliferation, apoptosis, and atherosclerosis by enhancing p53 activity. Circulation 130:1452-65
Saadatpour, Assieh; Guo, Guoji; Orkin, Stuart H et al. (2014) Characterizing heterogeneity in leukemic cells using single-cell gene expression analysis. Genome Biol 15:525
Pinello, Luca; Lo Bosco, Giosue; Yuan, Guo-Cheng (2014) Applications of alignment-free methods in epigenomics. Brief Bioinform 15:419-30
Pinello, Luca; Xu, Jian; Orkin, Stuart H et al. (2014) Analysis of chromatin-state plasticity identifies cell-type-specific regulators of H3K27me3 patterns. Proc Natl Acad Sci U S A 111:E344-53
Bauer, Daniel E; Kamran, Sophia C; Lessard, Samuel et al. (2013) An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level. Science 342:253-7
Ku, Wai Lim; Girvan, Michelle; Yuan, Guo-Cheng et al. (2013) Modeling the dynamics of bivalent histone modifications. PLoS One 8:e77944

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