# Epigenetic regulation of keratinocyte function in normal and pathologic skin repair

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $43,027

## Abstract

PROJECT SUMMARY/ABSTRACT
Non-healing wounds in patients with Type 2 Diabetes (T2D) are a major cause of morbidity and mortality and
are increasing at an alarming rate. Failure of wound healing in T2D patients represents the most common cause
of amputation in the US with a 5-year mortality rate of nearly 50%. Thus, a critical need exists for understanding
the wound healing defects in T2D in order to develop targeted therapies. We will utilize both genetic (db/db) and
dietary (diet-induced obese) murine models of T2D as well as human wound tissue and blood samples collected
from T2D patients to explore mechanisms of impaired wound healing. We present data using human single cell
RNA sequencing and murine diabetic wound models, that the repressive histone methyltransferase, SETDB2,
is decreased in diabetic wound keratinocytes resulting in increased production of inflammatory genes, namely
TNFα. Further, we have identified that interferon-beta (IFNꞵ), via a janus kinase (JAK1) / signal transducer and
activator of transcription (STAT) mechanism induces SETDB2 in wound keratinocytes. Our preliminary data also
identified that IL-17A is increased in diabetic wounds and may, in addition to reduced levels of IFNꞵ in diabetic
wounds, suppress SETDB2 in diabetic wound keratinocytes. These results have led to our hypothesis that
induction of SETDB2 in wound keratinocytes represses expression of NFkB-mediated genes (i.e., TNFα) that
maintain wound inflammation and directly impair keratinocyte migration, thereby promoting tissue repair. We
postulate that in diabetic wounds, it is the failure to induce SETDB2 and repress NFκB-mediated inflammatory
(Tnfα) genes in keratinocytes that prevents resolution of inflammation and impairs keratinocyte migration and
results in poor wound healing. We will test our hypotheses through three specific aims: Aim 1: To define the in
vivo regulation of NFκB-mediated gene expression by SETDB2 in normal and diabetic wound keratinocytes. Aim
2: To determine the JAK/STAT-mediated mechanism(s) that regulate keratinocyte-specific SETDB2 expression
in normal and diabetic wound tissue. Aim 3: To examine the therapeutic efficacy and timing of SETDB2-regulated
TNFα inhibition on keratinocyte migration and inflammatory wound Mφ phenotype. In this translational approach,
our data will pave the way for the development of promising therapeutic agents aimed at the targeting of
epigenetic pathways that mediate diabetic wound keratinocyte function and thereby promote diabetic wound
repair.

## Key facts

- **NIH application ID:** 10817026
- **Project number:** 5F31DK136199-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jadie Moon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,027
- **Award type:** 5
- **Project period:** 2023-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817026

## Citation

> US National Institutes of Health, RePORTER application 10817026, Epigenetic regulation of keratinocyte function in normal and pathologic skin repair (5F31DK136199-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10817026. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*