# Epigenetic regulation of epidermal proinflammatory responses

> **NIH NIH R56** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $404,975

## Abstract

ABSTRACT
It has been argued that keratinocytes at the interface of the body with the outside world have developed
specialized mechanisms to fulfill the need to nimbly respond to an ever-changing array of challenges with rapid
and reversible gene activation. Our past studies support the hypothesis that signaling information pertaining to
skin environmental insults is rapidly translated at repressed enhancers of stress response genes into chromatin
changes leading to their temporary induction. We have shown that the Mi-2β/NuRD complex sets a chromatin
environment that restricts transcription at genes that will be induced in keratinocytes by stress signals, holding
them silent but poised for rapid activation. Our studies highlight a dynamic switch between chromatin remodelers
that restrict gene expression and early response factors that support transcriptional activation. The mechanisms
that support this temporal switch and their contribution to response memory are investigated.
In Aim 1, we study how Mi-2β/NuRD is tethered to stress response loci in homeostasis, removed during
the stress response, and returned during resolution. We test whether Mi-2β/NuRD is targeted to these loci
by stable association with TFs, using both unbiased approaches and a focused approach on the AP1 complex.
We characterize post-transcriptional modifications (PTMs) of Mi-2β/NuRD or functionally associated TFs during
the early stress response, and test whether these have functional consequences on and off chromatin. We ask
how changes in the composition of the AP1 complex composition at target loci contribute to Mi-2β/NuRD complex
displacement and return, and whether enduring changes in TF occupancy at the loci or PTMs contribute to
epigenetic memory of the stress response. We examine how specificity is achieved by examining Mi-2β target
loci that are regulated by different TFs that do not respond to stress signaling.
In Aim 2, we investigate how histone modifications and higher order chromatin conformations contribute
to induction, repression, and reactivation of stress response genes in keratinocytes. We test for changes
in local histone modifications and TF recruitment at stress response genes and whether these contribute to the
memory of the response, defined as accelerated kinetics and increased magnitude of the response upon
rechallenge. We examine long-distance interactions between stress response enhancers, affiliated promoters,
and CTCF architectural sites, whether these are already present prior to stress, if they actively form in response
to it, and whether changes are maintained at some loci to alter activation thresholds as a mechanism of
epigenetic memory. Targeted manipulation of Mi-2β/NuRD and AP1 complex occupancy at specific loci is
employed to test their role in directing chromatin contacts and histone modifications at rest and during the
response. We also examine the heterogeneity of chromatin accessibility among basal cell precursors, its
heritability ...

## Key facts

- **NIH application ID:** 10933033
- **Project number:** 5R56AR082402-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** KATIA GEORGOPOULOS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $404,975
- **Award type:** 5
- **Project period:** 2023-09-22 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933033

## Citation

> US National Institutes of Health, RePORTER application 10933033, Epigenetic regulation of epidermal proinflammatory responses (5R56AR082402-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10933033. Licensed CC0.

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