Document Type

Dissertation

Date of Degree

Fall 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Genetics

First Advisor

Gai Tan

First Committee Member

Kai Tan

Second Committee Member

Aloysius Klingelhutz

Third Committee Member

Scott Moye-Rowley

Fourth Committee Member

Richard Smith

Fifth Committee Member

Hai-hui Xue

Abstract

Hematopoietic stem cell (HSC) development is accompanied by dynamic changes in the transcriptional program. How the corresponding transcriptional programs are related to the epigenetic mechanism is poorly understood.

To fill this gap, we first profiled the transcriptomes and epigenomes using RNA-Seq and ChIP-Seq for five key developmental stages of HSC emergence in the mouse embryo. Using epigenetic markers, we identified novel 12,000~17,000 enhancers for each developmental stage. We applied a computational tool to link those enhancers to their target genes. Systematical analysis of enhancer-promoter (EP) pairs using network-based strategy reveals multiple novel key transcription factors for early specification of HSC in the mouse embryo.

Second, we compared the 3D genome organization, epigenomes, and transcriptome of fetal and adult HSCs in the mouse. We found that higher-order genome structures are largely conserved between fetal and adult HSCs, including chromosomal compartments and topologically associating domains (TADs). However, chromatin interactions within TADs exhibit substantial differences. We found that promoters within 23% (242/1039) of TADs undergo interaction changes. Transcription factor motif analysis of HSC-specific enhancer-promoter loops suggests a role of KLF1 in mediating condition-specific enhancer looping and regulation of genes involved in cell cycle. Our result provides a comprehensive view of the differences in 3D genome organization, epigenome, and transcriptome between fetal and adult HSCs.

Keywords

ChIP-Seq, enhancer-promoter interaction, epigenetics, genome organization, hematopoietic stem cells, transcriptional program

Pages

xvii, 167 pages

Bibliography

Includes bibliographical references (pages 147-167).

Comments

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Copyright

Copyright © 2017 Changya Chen

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Genetics Commons

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