# The role of Tet1 in myofibroblast differentiation

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $606,430

## Abstract

Project Summary:
Myofibroblasts are differentiated mesenchymal cells with identified roles in development, cancer, tissue
repair/remodeling. Regulation of myofibroblast differentiation involves multiple signaling pathways and
respective downstream transcription factors as well as significant modulation by epigenetic factors such as
DNA methylation. Abundant studies focused on identification of transcription factors and their role in regulation
of the α-smooth muscle actin (Acta2) gene as a marker of differentiation, but the mechanism of epigenetic
regulation is not as well understood. Select CpG islands in the Acta2 gene are differentially methylated in
myofibroblasts vs. fibroblasts and epithelial cells. Impairment of DNA methylation enhances differentiation
while the converse inhibits differentiation. Active demethylation by the Tet (Ten-eleven translocation) proteins,
which are methylcytosine dioxygenases, is implicated in cell differentiation. Their importance in cell
differentiation is suggested in studies of embryonal and other stem cells, but their significance in regulation of
myofibroblast differentiation is unknown. Preliminary data showed selective induction of Tet1 and not the other
2 isoforms (Tet2 and Tet3) in myofibroblast differentiation, while Tet1 deficiency caused impaired differentiation
both in vivo and in vitro. Thus the selective importance of the Tet1 isoform is suggested in differentiation. While
Tet1 does not globally regulate all genes by demethylation, the identity of at least one Tet1 regulated target
gene, Acta2 could be inferred from the preliminary data. Based on the previous findings and preliminary data
we hypothesized that Tet1 importantly regulates myofibroblast differentiation by demethylation of regulatory
DNA sequences in select target genes essential for the differentiation process. Select recruitment to the
relevant target DNA sequences is mediated by Tet1 binding proteins/transcription factors with binding
specificity for these DNA regions. To test this hypothesis the Specific Aims are as follows, 1) to screen for and
identify Tet1 target genes important in myofibroblast differentiation in fibroblasts, 2) to study the mechanism of
Tet1 regulation of key target genes essential for myofibroblast differentiation, and 3) to assess the in vivo
significance of Tet1 regulation of myofibroblast differentiation. The studies will use epigenomic approaches to
assess differentially methylated genes and transgenic mice to evaluate the biological importance of Tet1 and
select differentiation relevant genes in specific cell types in vivo. Achievement of the goals will shed new light
on the epigenetic regulation of myofibroblast differentiation of relevance to development, cancer and tissue
repair/remodeling.

## Key facts

- **NIH application ID:** 10201053
- **Project number:** 1R01HL143339-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** SEM H PHAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $606,430
- **Award type:** 1
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201053

## Citation

> US National Institutes of Health, RePORTER application 10201053, The role of Tet1 in myofibroblast differentiation (1R01HL143339-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10201053. Licensed CC0.

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