# Epigenetic regulation of proinflammatory responses in the skin

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $362,858

## Abstract

ABSTRACT
We have shown that loss of the chromatin remodeler Mi-2β in the basal epidermis causes
rapid up-regulation of pro-inflammatory and stress response genes in the absence of any
overt environmental signals or a skin barrier defect. These data support the hypothesis that
immune cell regulatory genes, normally induced in the epidermis by environmental insults,
are directly and actively repressed by chromatin regulators, under conditions of epidermal
homeostasis. We now propose to study the chromatin-based mechanisms by which
immune-regulatory genes are kept poised for expression in keratinocytes and to determine
how activation of signaling pathways by mechanical or environmental insult reverses these
mechanisms.
In the first aim, we will establish the “anti-inflammatory” chromatin landscape and
transcription factor network that control keratinocyte homeostasis. Genome-wide
approaches will be used in keratinocytes to establish the gene networks that are directly
and functionally controlled by Mi-2β. The types of regulatory elements that Mi-2β associates
with, and the chromatin configuration that they are in will be established. The sequence-
specific DNA binding factors that functionally interact in a synergistic or antagonistic fashion
with Mi-2β will be identified. Finally, the repertoire of chromatin regulators and transcription
factors involved in pro-inflammatory gene regulation in a Mi-2β−independent fashion will be
also established.
In the second aim, we will determine how environmental signals induce pro-
inflammatory gene expression in keratinocytes. The effect of environmental signals on
altering the activity of both chromatin regulators and transcription factors will be studied.
We will first examine the cause-effect relationship between Mi-2β and the epigenetic and
transcription factor makeup at the regulatory domains of its target genes. We will then test
how environmental signals induce pro-inflammatory genes by altering the activities of Mi-
2β and associated chromatin regulators and transcription factors. The role of key
regulatory candidates in this molecular process will be further evaluated by genetic
interference studies in mouse and human keratinocytes.
The outcome of these studies will allow us to probe into conserved mechanisms that
contribute to human skin disease with a pro-inflammatory basis and provide new avenues
for therapeutic intervention.

## Key facts

- **NIH application ID:** 9950988
- **Project number:** 5R01AR069132-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** KATIA GEORGOPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,858
- **Award type:** 5
- **Project period:** 2016-07-11 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9950988

## Citation

> US National Institutes of Health, RePORTER application 9950988, Epigenetic regulation of proinflammatory responses in the skin (5R01AR069132-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9950988. Licensed CC0.

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