# Transcriptional control of microglia diversification and inflammation

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $398,325

## Abstract

Project Summary
Our proposal focuses on the epigenetic mechanisms of microglia-mediated regulation of brain homeostasis
and neuro-degeneration. Our recent studies revealed brain region-specific microglia specification and
suggested that this specification matches distinct neuron phenotypes in functionally distinct brain areas. We
showed that regional microglia specification depends on the Polycomb Repressive Complex 2 (PRC2),
which silences microglia genes in a brain-region specific fashion. Ablation of PRC2 “relaxes” specification
of microglia followed by neurodegenerative-like changes in neuronal function and behavior. These findings
suggest a model where interaction between “matching” neurons and microglia renders microglia from the
aberrant production of factors responsible for microglial-mediated neuronal damage. To test our hypothesis,
we propose to identify PRC2 targets in microglia in different brain regions and to determine the impact of
PRC2 inactivation on regional microglia specification. PRC2 has been shown to operate downstream of
different signaling pathways including the RAF/Erk signaling pathway, which has been implicated in
microglia-mediated neurotoxicity. We hypothesize that activation of these signaling pathways may trigger
the aberrant expression of genes controlling microglia proliferation, phagocytosis and/or proinflammatory
activity by directly affecting PRC2 function. We will address the link between signal-induced microglia-driven
neurotoxicity and PRC2-mediated gene silencing.
Much of the microglia-mediated toxicity during neurodegeneration involves the activation of inflammatory
responses. Our proposal aims at identification of the gene regulatory mechanisms supporting the
proinflammatory activity of microglia. We found that BET proteins, which link histone acetylation and
activation of RNA Pol II, play a key role in the signal-induced transcription of proinflammatory genes in
microglia. We show that the pharmacological inhibition of BET leads to the selective suppression of microglia
inflammatory gene expression in vitro and in vivo. The BET family includes the structurally different BRD2,
BRD3 and BRD4 proteins, all of which are expressed in microglia. We previously observed differential
binding of individual BET proteins to distinct gene targets in macrophages and neurons. Using mice with
conditional microglia-specific inactivation, we will determine the contribution of individual BET proteins to
brain region-specific microglia phenotypes in the healthy brain and during neurodegeneration. In summary,
the proposed research will identify novel epigenetic mechanisms of region-specific microglia specification
and the contribution of these mechanisms to neurodegeneration. Identification of proteins controlling distinct
states of microglia activity will facilitate the development of novel therapeutic approaches for the prevention
and/or attenuation of neurodegeneration.

## Key facts

- **NIH application ID:** 10110033
- **Project number:** 5R01NS106721-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Anne Schaefer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,325
- **Award type:** 5
- **Project period:** 2020-03-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10110033

## Citation

> US National Institutes of Health, RePORTER application 10110033, Transcriptional control of microglia diversification and inflammation (5R01NS106721-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10110033. Licensed CC0.

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