Decoding Chromatin Accessibility Programs In Cancer
| dc.contributor.advisor | Leslie, Christina | |
| dc.contributor.author | Chhangawala, Sagar | |
| dc.date.accessioned | 2019-03-26T19:19:02Z | |
| dc.date.available | 2021-02-04T07:00:42Z | |
| dc.date.issued | 2019 | |
| dc.description.abstract | Chromatin accessibility plays an important role in defining cell identity and phenotype. With the emergence of novel methods like ATAC-seq, a sequencing method that maps regions of open chromatin and enables the computational analysis of transcription factor (TF) binding at chromatin accessible sites, we can start to dissect the regulatory landscape in cancer. I present two vignettes that use ATAC-seq to analyze the phenotypes of tumor: 1. Pancreatic cancer is expected to become the 2nd deadliest cancer by 2020 in the US, and few therapeutic options are currently available. Additionally, 50% of pancreatic cancer patients recur within just one year. Previous genomic analyses of pancreatic tumors, including somatic mutation mapping and gene expression profiling, did not explain this difference in recurrence. We hypothesized that epigenetic heterogeneity underlies previously described difference in recurrence. We sorted 54 fresh patient tumor samples based on EpCAM (an epithelial cell marker) to enrich for tumor cells and subjected them to ATAC-seq. Using supervised learning and generalized linear modeling, we were able to characterize the changes in RNA-seq and ATAC-seq between recurrent vs non-recurrent patients. We characterized TF motifs in accessible peaks across all samples and used ridge regression to identify differential TF activity enriched in recurrent patients. Two TF hits, ZSCAN1 and HNF1b, were experimentally validated to predict recurrence in our cohort and in an independent cohort. These results reveal a novel regulatory landscape in recurrent patients of pancreatic cancer and support the development of individualized therapies. 2. Approximately 70% of breast cancers express estrogen receptor (ER) and are treated with ER-blocking endocrine therapy (e.g. fulvestrant). Despite the efficacy of such treatments, resistance to anti-hormonal therapy remains a clinical challenge. We performed an epigenome-wide CRISPR knockout screen on MCF7 ER-positive breast cancer cells, and identified ARID1A to be the top candidate whose loss limits the sensitivity to fulvestrant. To uncover how ARID1A loss confers fulvestrant resistance, we undertook a chromatin-based approach. Analysis from ATAC-seq and RNA-seq assays showed that loss of ARID1A leads to a widespread chromatin remodeling of the breast cancer epigenome to regulate the binding of a series of TF that in concert alter gene expression profiles. This results in a switch from luminal cells to ER independent basal-like cells, which has adverse prognosis for patients on hormone therapy. | |
| dc.identifier.uri | https://hdl.handle.net/1813/64823 | |
| dc.language.iso | en_US | |
| dc.rights | Attribution-NonCommercial-NoDerivatives 4.0 International | |
| dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject | ATAC-seq | |
| dc.subject | breast cancer | |
| dc.subject | Cancer biology | |
| dc.subject | chromatin accessibility | |
| dc.subject | epigenetics | |
| dc.subject | pancreatic cancer | |
| dc.title | Decoding Chromatin Accessibility Programs In Cancer | |
| dc.type | dissertation or thesis | |
| thesis.degree.discipline | Physiology, Biophysics & Systems Biology | |
| thesis.degree.grantor | Weill Cornell Graduate School of Medical Sciences | |
| thesis.degree.level | Doctor of Philosophy |
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