Date of Award
2026
Document Type
Thesis
Degree Name
Doctor of Philosophy (PhD)
Thesis Advisor
Elaine Fuchs
Abstract
Adaptation is essential for survival in an ever-inflammatory world of injuries, irritants, and infections. Initially thought to be the sole purview of antigen-specific lymphocytes, biologists now appreciate that nearly every cellular compartment in the body has the capacity to epigenetically remember its inflammatory past. The consequences are central to tissue and organismal health, allowing for rapid protection against a breadth of future stresses – including ones never seen before – while also heightening sensitivity to severe chronic inflammatory diseases and cancer. In this dissertation, I use the skin as a model tissue to elucidate two fundamental yet poorly understood properties of such tissue inflammatory adaptations. First, I investigate how long epigenetic memories last in epidermal stem cells exposed to a psoriasis-like flare, and the cell-intrinsic mechanisms therein that govern their endurance versus erosion. I discover that memory longevity is controlled by CpG density, which upon stress potentiates DNA demethylation and acquisition of the nucleosome-destabilizing histone variant H2A.Z. As such, a subset of key stress-response genes acquire a stable epigenetic unit that, as I discover, can be transmitted across cellular generations to endow functional hypersensitivity for the lifetime of a mouse. Extending these findings to other inflammatory contexts, I provide suggestive evidence that this mechanism of longevity may serve as a broadly applicable and evolutionarily conserved form of long-term stress adaptation. In the second part of this dissertation, I then explore how a localized atopic dermatitis-like flare systemically shapes the future fitness of the entire skin tissue. I discover that both inflammation-experienced and distal skin acquire marked and comparable advantages in their ability to heal future wounds, despite their vastly different inflammatory experiences. Tissue-wide training relies on the ability of the skin to acutely sense circulating alarmins from distally stressed sites. This response in turn leads to an enduring, barrier-wide hypersensitization of epidermal tissue stem cells, which persistently heighten stemness-associated transcriptional programs but do so in the marked absence of changes to chromatin accessibility. Altogether, the body of work presented in this thesis describes new principles by which tissues adapt over time and space to the inflammatory pressures of their outside worlds.
License and Reuse Information
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Recommended Citation
Sajjath, Sairaj Munavar, "Duration and Dissemination of Tissue Inflammatory Memories" (2026). Student Theses and Dissertations. 864.
https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/864
Comments
A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy