Student Theses and Dissertations

Date of Award

2019

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Fuchs Laboratory

Abstract

As one of the body’s largest environmental interfaces, the skin is routinely exposed to a myriad of inflammatory stimuli. It functions as a barrier acting as the first line of defense against pathogens, while simultaneously protecting the organism from dehydration. Maintaining an intact barrier is therefore paramount to organismal survival, and the foremost torchbearers of this task are skin epithelial stem cells (EpSCs). EpSCs reside in the basal layer of the skin, survive long-term, and are capable of both self-renewing and differentiating into multiple skin lineages. To efficaciously maintain the barrier, EpSCs must be able to sense and respond to environmental cues. Here, I unearth an adaptive mechanism whereby EpSCs retain an epigenetic memory of prior inflammatory exposure that endows them with enhanced sensitivity and responsiveness to subsequent tissue damage. During secondary injury, inflammatory memory is mediated by cytosolic dsDNA sensor and activator of the inflammasome AIM2, and its downstream effectors caspase-1 and interleukin-1. Characterization of the chromatin landscape in inflammation-experienced EpSCs reveals specific retention of monomethylation of histone 3 on lysine 4 in memory chromatin domains primed for reactivation. Altogether, this body of work identifies a novel mechanism by which EpSCs cope with and adapt to environmental stress in preparation for the next inflammatory trigger.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

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