Understanding DNA Methylation and Nucleosome Organization In Cancer Cells

Speaker: Yaping Liu , USC Epigenome Center, Genetics/MCB program

Date: Monday, April 28, 2014

Time: 1:00 PM to 2:00 PM Note: all times are in the Eastern Time Zone

Public: Yes

Location: MIT Stata Center, 8th Floor, Gates Tower, 32G-882, 32 Vassar St., Cambridge MA

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Host: Manolis Kellis, MIT

Contact: Manolis Kellis, 617-253-2419, manoli@mit.edu

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Reminders to: talks@broad.mit.edu, seminars@csail.mit.edu

Reminder Subject: TALK: Understanding DNA Methylation and Nucleosome Organization In Cancer Cells

Understanding DNA Methylation and Nucleosome Organization In Cancer Cells Using NOMe-seq

Yaping Liu, PhD candidate
USC Epigenome Center
Genetics Molecular and Cellular Biology Program
University of Southern California

One of the hallmarks of cancer is aberrant epigenetic changes which include alterations in DNA methylation, nucleosome positioning and histone modifications. DNA methylation changes have been studied extensively. However, their relationship to other epigenetic changes and the genome-wide organization of chromatin structure in cancer remain unclear. We developed a method (NOMe-seq) that uses a GpC methyltransferase (M.CviPI ) and next generation sequencing to generate a high resolution footprint of nucleosome positioning genome-wide while retaining endogenous DNA methylation information from the same DNA strand.

Single-nucleotide polymorphisms (SNPs) can result in inaccurate or missing methylation calls in Bisulfite-seq/NOMe-seq, I developed Bis-SNP based on the Genome Analysis Toolkit (GATK) framework which uses bayesian inference to determine genotypes and methylation/accessibility levels simultaneously. I also developed a segmentation method based on beta-binomial Hidden Markov Model to identify individual nucleosomes and Nucleosome Depleted Regions (NDRs) for NOMe-seq. Furthermore, we applied EM algorithm on NOMe-seq to exploit the single molecule nature for the discovery of discrete subpopulations with different epigenetic patterns in cancer.

Using the experimental and computational methods developed above, we evaluated the functional interactions between DNA methylation and other epigenetic modifiers at a genetic knockout of DNMT3B and DNMT1 (DKO1) in human colon cancer cells (HCT116). We observed an increase of gene expression and widespread chromatin remodeling which accompany the global hypomethylation in DKO1 cells when compared to its parent cells. Interestingly, changes in DKO1 cells occur in a direction such that the cells gain an epigenetic landscape and gene expression similar to normal colonic mucosa. Taken together, these changes suggest that chromatin remodeling occur in the absence of DNA methylation and may provide insights into the crosstalk between epigenetic mechanisms in cancer.

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Created by Manolis Kellis Email at Sunday, April 20, 2014 at 7:14 PM.