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dc.contributor.advisorPillai, Shiv
dc.contributor.advisorOrkin, Stuart H.
dc.contributor.authorBeyaz, Semir
dc.date.accessioned2018-12-20T08:11:28Z
dc.date.created2017-03
dc.date.issued2017-01-26
dc.date.submitted2017
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:37945008*
dc.description.abstractA fundamental question in biology is to decipher how the same genomic information in an organism can give rise to diverse cellular states that are phenotypically and functionally distinct. Epigenetic mechanisms utilize genomic information to establish unique gene expression patterns that cells acquire in different fates during development or in response to environmental perturbations such as diet. Although it is understood that a particular cell fate-specific gene expression pattern relies on the establishment of a specific chromatin organization that is shaped by the activities of chromatin-modifying enzymes and transcription factors, the precise mechanisms that they employ for epigenetic regulation during cellular differentiation and in response to diet are unclear. Here, we dissect the mechanisms underlying epigenetic regulation of cell fate in two different models: regulation of iNKT cell development by the H3K27me3 histone demethylases and dietary regulation of intestinal stem cell fate. First, we interrogated the biological significance of H3K27me3 histone demethylases (UTX and JMJD3) during iNKT development. iNKT cells are innate-like lymphocytes that protect against infection, autoimmune disease, and cancer. We showed that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. Notably, we identified JunB as a novel regulator of iNKT development and showed that target genes of both JunB and iNKT master transcription factor PLZF are UTX-dependent. Moreover, we demonstrated that UTX-mediated regulation of super-enhancer accessibility is a key mechanism for iNKT lineage commitment. Altogether, these findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms. Second, we assessed the cellular and molecular mechanisms through which pro-obesity diets regulate tissue stem and progenitor cell function. We showed that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells of the mammalian intestine. Mechanistically, we found that a HFD activated the lipid-sensing transcription factor peroxisome proliferator-activated receptor delta (PPAR-δ) in intestinal stem cells and progenitor cells (non-intestinal stem cells) and pharmacological activation of PPAR-δ recapitulated the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhanced the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endowed organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permitted these progenitors to form in vivo tumors after loss of the tumor suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors. Overall, these studies delineate the epigenetic mechanisms that control cell state-specific gene expression patterns through the regulation of transcription by histone-modifying enzymes and transcription factors.
dc.description.sponsorshipMedical Sciences
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectHealth Sciences, Immunology
dc.titleEpigenetic Regulation of Cell Fate
dc.typeThesis or Dissertation
dash.depositing.authorBeyaz, Semir
dc.date.available2018-12-20T08:11:28Z
thesis.degree.date2017
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberShivdasani, Ramesh A.
dc.contributor.committeeMemberHaining, Nicholas
dc.type.materialtext
thesis.degree.departmentMedical Sciences
dash.identifier.vireohttp://etds.lib.harvard.edu/gsas/admin/view/1365
dc.description.keywordsEpigenetics; stem cells; immunology; cancer
dc.identifier.orcid0000-0003-4730-4012
dash.author.emailsemirbeyaz@gmail.com


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