THE INFLUENCE OF CHROMATIN STATE ON PLURIPOTENCY, TRANSLOCATIONS, AND GENE REGULATION IN HUMAN CELLS

Zhang, Zhuzhu

THE INFLUENCE OF CHROMATIN STATE ON PLURIPOTENCY, TRANSLOCATIONS, AND GENE REGULATION IN HUMAN CELLS

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March 20, 2019

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Zhang, Zhuzhu
- Affiliation: School of Medicine, Curriculum in Bioinformatics and Computational Biology

Abstract

A human body consists of more than a thousand cell types, each having a unique identity and function. Despite their distinct functions, all the different cells contain the same genetic information encoded in the human genome. One of the fundamental questions in biology is- how does a single genome provide the instruction for different cell types? We have learned that only a small part of the genomic information is used in each cell, and that the usage of the genome varies in different cells. The precise regulation of the genome usage is the key to cell identity. The usage of the genomic information highly depends on whether the DNA sequence containing specific information is directly accessible to DNA-binding proteins such as transcription factors that read and translate the encoded information. Most of the genomic DNA wrapped around histone proteins, forming the nucleosomes. Most DNA-binding proteins cannot bind to their target DNA sequences if a nucleosome is present. Therefore, the nucleosome-depleted regions, open chromatin, represent regions of the genome that are accessible and the genomic information that is used in the cell. In this dissertation, I study the landscape and function of open chromatin, and its role in defining cell identity and function. I examine the open chromatin architecture in a specific case of cell identity - the reestablishment of pluripotency in terminally differentiated cells by reprogramming the cell fate (Chapter II). Induced pluripotent stem cells (iPSCs) are reprogrammed from differentiated somatic cells. Compared to their naturally existing counterpart embryonic stem cells (ESCs), iPSCs have very similar but in many cases slightly altered developmental potential when differentiating into other cell types. The cause of the different development potential is poorly understood. In this study, I show that the regulatory landscape defined by open chromatin is highly similar between hESCs and hiPSCs but differs at a set of key development genes. More importantly, the chromatin differences do not appear to affect the transcription profiles at the pluripotent state, but instead impact the regulation of transcription upon differentiation. These results suggest that the accessibility of genomic information controlled by chromatin structure does not only regulate the cell identity at its current state, but also influence the precise regulation of its developmental potential. In addition, I describe a high-throughput method I developed for functional annotation of the regulatory elements marked by open chromatin (Chapter III). Using this approach, I identified 3,428 open chromatin regions associated with enhancer activities in a reporter assay, demonstrating the feasibility of functional characterization of several thousand regulatory elements in a single experiment of this design. At last, I investigate the role of chromatin structure in the development of cancer (Chapter III). The results indicate that characteristic chromatin features marked by specific histone modifications may highlight genomic loci that are susceptible to chromosomal translocation in hematologic malignancies.

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