# Histone lactylation pathway in hair cycle: deacylases and their protein targets

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $675,539

## Abstract

Emerging lines of evidence suggest an intimate crosstalk among energy metabolism, metabolites and
epigenetics. Post-translational modifications (PTMs) on histones (histone “marks”) (e.g., lysine acetylation
(Kac) and methylation (Kme)) are known to be regulated by metabolism, contributing to the epigenetic
programs that are associated with cellular physiology and disease. However, we do not yet know if additional
histone PTM pathways exist and if they can be modulated by diverse cellular metabolites. Thus, chemistry and
biochemistry of metabolites-mediated chromatin changes remain poorly characterized. Lactate, a widely known
cellular metabolite, can be dramatically induced under some cellular conditions (e.g. hypoxia) and in the
Warburg effect, an observation most commonly shared among diverse cancers and associated with many
diseases. Lactate concentration can rise to 20-40 mM in cancer tissues. Although this compound was
discovered ~200 years ago, its non-metabolic functions in physiology (e.g., hypoxia, stem cell differentiation
and immunoresponse) and disease (e.g., cancer and diabetes) remain unknown, representing a long-standing
question in biology. We recently discovered a lactate-derived, new lysine modification, lysine lactylation (Kla).
We comprehensively validated this PTM by chemical and biochemical approaches. This PTM can be
stimulated by the Warburg effect-derived lactate and has different temporal dynamics from the widely studied
lysine acetylation (Kac). Our epigenetic studies suggest that histone Kla represents a new type of metabolism-
regulated epigenetic changes and contributes to gene regulation. We hypothesize that the histone Kla pathway
is molecularly distinct from Kac pathway and contribute to gene regulation. We therefore propose to
characterize the Kla pathway by defining its key regulatory elements: enzymes that can remove the
modification (or delactylases), and their targets on histones and non-histone substrate proteins. We will also
study their role in epigenetic regulation in cyclic behavior of hair follicle stem cells (HFSCs) in which lactate and
its regulatory enzyme play a key role. We will use an integrated strategy involving chemical biology,
enzymology, quantitative proteomics, and biochemistry approaches. The knowledge gained from this study will
likely have a broad impact on our understanding of epigenetics, and will lay a foundation for studying Kla and
the Warburg effect.

## Key facts

- **NIH application ID:** 10412929
- **Project number:** 5R01AR078555-02
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Hening Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $675,539
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412929

## Citation

> US National Institutes of Health, RePORTER application 10412929, Histone lactylation pathway in hair cycle: deacylases and their protein targets (5R01AR078555-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10412929. Licensed CC0.

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