# Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2021 · $423,500

## Abstract

Astrocytes play an indispensable role in maintaining a healthy environment for neuronal function, and in
mediating the response of the CNS to injury. Following an injury astrocytes become “reactive” and mediate both
helpful and harmful outcomes depending on their gene expression profile. However the molecular mechanisms
that regulate gene expression in astrocytes and thus their response to injury has not been fully delineated. One
protein that plays a key role in regulating the response of astrocytes to insults is transglutaminase 2 (TG2).
Deletion or depletion of TG2 results in astrocytes taking on a more “helpful” phenotype, however the underlying
molecular mechanisms are unknown. TG2 is a multifunctional protein; it catalyzes a calcium dependent
transamidation reaction, binds and hydrolyzes GTP and can function as a scaffold or linker protein. TG2
undergoes large conformational changes mediated by calcium and GTP binding, and its conformation can dictate
its function independent of its enzymatic activities. These conformational states are key a factors in determining
cell survival/cell death outcomes. There is a growing awareness that TG2 likely regulates gene expression,
however the mechanisms of TG2-mediated regulation of gene expression in astrocytes has not been fully
explored. One possible mechanism may be by TG2 interacting with, and modulating the function of, a protein
that plays a pivotal role in regulating gene expression. One factor that plays a key role in regulating chromatin
accessibility and the activity of specific transcription factors is Zbtb7a. Intriguingly, preliminary data indicate that
TG2 interacts with Zbtb7a, and binding sites for these transcription factors are in the majority of pro-survival
genes that are upregulated in TG2-/- astrocytes. The UNDERLYING PREMISE of this proposal is that TG2 plays
a role in regulating gene expression in astrocytes, and thus how they respond to injury. However, a CRITICAL
KNOWLEDGE GAP is how TG2 regulates gene expression. The OVERALL HYPOTHESIS of this application
is that TG2, in a conformational dependent manner, moderates chromatin accessibility and the gene expression
landscape, which contributes to how astrocytes respond to injury. The NOVELTY of this project is that we will
be using an integrated “omic” approach (ATAC-seq, RNA-seq, ChIP-seq) and both in vitro and in vivo models of
TG2+/+ and TG2-/- astrocytes to establish the mechanisms by which TG2 in a specific conformation regulates
gene expression. The specific aims of this proposal are to test the hypothesis that: (1) the conformation of TG2
play an essential role in determining its ability to regulate chromatin accessibility and gene expression, and (2)
TG2 mediates gene expression in astrocytes in part by regulating the function of Zbtb7a. The data generated
from these novel and exploratory studies will provide the basis for a future R01 grant application focused on
delineating the molecular mechanisms and pathways regulat...

## Key facts

- **NIH application ID:** 10293984
- **Project number:** 1R21NS119673-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Gail V. W. Johnson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $423,500
- **Award type:** 1
- **Project period:** 2021-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10293984

## Citation

> US National Institutes of Health, RePORTER application 10293984, Mechanisms of Transglutaminase 2 (TG2)-Mediated Gene Expression in Astrocyte (1R21NS119673-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10293984. Licensed CC0.

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