# KLF-mediated coordination of signaling and epigenetic mechanisms in the skin

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2020 · $372,900

## Abstract

Project Summary
Regenerative processes in the skin require cross-talk of multiple cell signaling and epigenetic mechanisms;
failure of this communication leads to a range of diseases from skin cancers to hair loss conditions. Delineating
how these inputs are coordinated to impact gene expression at the level of chromatin has potential to identify
novel therapies for skin dysfunction. Pioneer transcription factors initiate gene expression by binding
nucleosome-enriched silent chromatin and recruiting chromatin modifiers to provide access for transcription
machinery. Key regulatory genes in hair follicle stem cells are associated with “super enhancers” containing
binding sites for multiple transcription factors, suggesting that transcription factors activated in response to
diverse signals collaborate with each other and with chromatin modifiers to coordinate cell-type specific
transcriptional output. KLF4, a Krüppel-like family member, has well-established functions as a pioneer
transcription factor in iPS reprogramming, blocks Wnt/β-catenin signaling in intestinal epithelial cells, is
required for normal differentiation of interfollicular epidermis, and is highly expressed in hair follicle stem cells.
Opposite to KLF4, KLF5 promotes basal epidermal proliferation, and is required for Wnt/β-catenin signaling in
intestine. KLF4 and KLF5 can directly repress each other's expression and KLF5 is absent from quiescent hair
follicle stem cells, but is expressed in hair follicle matrix cells and in differentiating hair shaft cortex precursors
that are highly Wnt-active. The Aims of this proposal are: (1) to test the hypothesis that KLF4 integrates
multiple signals to maintain hair follicle stem cell quiescence by (i) directly activating hair follicle stem cell
quiescence genes, and (ii) complexing with TCF3/TCF4/HDAC to suppress Wnt targets; (2) to test the
hypothesis that mutually antagonistic KLF4 and KLF5 functions control key transitions of hair follicle stem cells
and their progeny. Genetic mouse models, and biochemical and genomics approaches will be used to address
these questions.

## Key facts

- **NIH application ID:** 9866864
- **Project number:** 1R01AR076428-01
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Sarah E. Millar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,900
- **Award type:** 1
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9866864

## Citation

> US National Institutes of Health, RePORTER application 9866864, KLF-mediated coordination of signaling and epigenetic mechanisms in the skin (1R01AR076428-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9866864. Licensed CC0.

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