Nucleosomes, the core components of chromatin, regulate transcription by blocking the access of DNA to transcription factors and RNA polymerases. Dysregulation of this process often leads to diseases like cancer. Next-generation sequencing has underscored the pivotal role of chromatin landscape alterations in cancer initiation, progression, and drug resistance, yet the underlying mechanisms linking chromatin structure to the transcription process remain unclear. Recent advances in nanopore long-read sequencing technology enable the profiling of chromatin accessibility in single-molecule long-read. The longer read length and higher resolution allow for the direct observation of nucleosomes spanning the entire gene, facilitating the study of nucleosome occupancy and its association with transcriptional processes such as transcription initiation, elongation, splicing, and termination. This unique advantage will help answer how alterations in chromatin accessibility and transcriptional processes contribute to cancer initiation and progression.

To address these questions, firstly, I propose to develop a neural network model to map chromatin accessibility in the yeast genome by identifying small molecule angelicin intercalation from nanopore long-read data. Secondly, I will identify changes in nucleosome positioning induced by mutations in ISW1 and CHD1, two important genes in chromatin remodelers, through nanopore sequencing of 6mA methylated yeast chromatin. I propose to investigate how alterations in nucleosome positioning impact transcription by integrating paired RNA sequencing data to link transcriptional changes with different nucleosome positioning configurations. Lastly, I will study how chromatin accessibility and RNA profiles are altered in lung adenocarcinoma cell lines with mutation in the mSWI/SNF chromatin remodeling complex, which is highly recurrent in over 25% of cancers.

Understanding the role of mSWI/SNF will provide insights into cancer-relevant transcription factors and oncogenic isoform signatures, which is essential for the development of targeted cancer therapies.
Beyond its implications for cancer therapeutics, this method could offer a more comprehensive view of how changes in chromatin structure impact gene regulation, advancing our understanding of chromatin dynamics in health and disease.

Event Host: Gali Bai, Ph.D. Student, Biomolecular Engineering & Bioinformatics

Advisor: Angela N. Brooks