Research

 NutriEpigenomics Lab conducts research on the mechanisms of metabolic changes through the regulation of genes related to nutrients or metabolites using multi-omics analyses such as genomics, transcriptomics, epigenomics, and metabolomics. By utilizing cellular differentiation models and genetically modified mouse models, the lab aims to elucidate the molecular regulatory mechanisms of nutrients or metabolites and identify molecular patterns associated with chronic diseases such as diabetes and cancer. Furthermore, our lab explores reversible regulatory strategies using nutritional substances.

  Current projects are the followings:  1) Epigenetic mechanisms underlying inheritance of metabolic imprinting, 2) Effects of macronutrients on Circadian clock regulation, and 3) Omics analysis on diabetes and cancer to identify biomarkers. 

1) Epigenetic Inheritance

Parental metabolic state can be transmitted to offspring through epigenetic mechanisms — a phenomenon with profound implications for the intergenerational propagation of metabolic disease. Our lab investigates how diet-induced metabolic stress in parents reshapes the epigenetic landscape of germ cells, ultimately programming the metabolic health of subsequent generations.

A central focus is the role of tRNA-derived fragments (tRFs) as potential carriers of metabolic memory in sperm. Using high-fat diet (HFD) mouse models and small RNA sequencing, we have shown that HFD-induced obesity significantly alters tRF profiles in the male germline — shifting the balance between 5'-derived and 3'-derived tRFs and implicating the ribonuclease angiogenin (encoded by Ang) and the energy sensor AMPK as upstream regulators of tRNA cleavage patterns. These findings suggest a mechanistic link between paternal metabolic stress and epigenetic inheritance via sperm small RNAs.

Earlier work from our lab demonstrated that paternal diet-induced obesity leads to metabolic dysregulation in offspring through endoplasmic reticulum (ER) stress in a sex-specific manner, and that branched-chain amino acid supplementation combined with HFD can produce transgenerational phenotypic effects.

Key publications:

• Lee E, Choi SY, Song S, Lindroth AM, Park YJ. AMPK inhibition and elevated angiogenin are associated with tRNA fragmentation in the male germline exposed to a high-fat diet, Mol Metab, 2026 Mar 12

• Park JH, Yoo Y, Cho M, Lim J, Lindroth AM, Park YJ. Diet-induced obesity leads to metabolic dysregulation in offspring via endoplasmic reticulum stress in a sex-specific manner, Int J Obes, 2017 Aug 16

2) Circadian Clock Regulation

The circadian clock governs nearly all physiological processes, and its disruption is closely linked to metabolic disease. Our lab explores how macronutrients — particularly dietary protein, fat, and carbohydrates — regulate the molecular clock, and how epigenetic mechanisms mediate this interaction.

We have shown that low dietary protein intake selectively disrupts peripheral circadian rhythms while leaving the central clock relatively intact, implicating amino acid sensing pathways (including FGF21 signaling) as key conduits linking nutrient availability to clock gene expression in peripheral tissues such as the liver. In parallel, we have demonstrated that the ratio of dietary fat to carbohydrates interacts with genetic variants in circadian genes (CLOCK, BMAL1, PER, CRY) to modulate obesity risk in human cohort data.

Beyond macronutrients, our lab has uncovered epigenetic mechanisms through which dietary bioactives modulate the clock. Butyrate, a short-chain fatty acid produced by gut microbial fermentation of fiber, was found to exert anti-obesity effects by modulating the gut microbiome and simultaneously increasing chromatin accessibility at core clock gene promoters in skeletal muscle via HDAC inhibition — linking diet, the microbiome, epigenetics, and circadian regulation in a single pathway. We have also demonstrated that NMN (nicotinamide mononucleotide) supplementation attenuates hepatic ER stress and restores circadian clock gene expression in diet-induced obese mice.

At the epidemiological level, we have shown that late meal timing and short sleep duration are independently associated with obesity incidence in a large Korean prospective cohort, supporting the translational relevance of our mechanistic findings.

Key publications:

• Han Y, Shon J, Kwon S, Park YJ. Effects of dietary protein intake levels on peripheral circadian rhythm in mice, Int J Mol Sci, 2024 Jul 5

• Shon J, Han Y, Song S, Kwon SY, Na K, Lindroth AM, Park YJ. Anti-obesity effect of butyrate links to modulation of gut microbiome and epigenetic regulation of muscular circadian clock, J Nutr Biochem, 2024 Feb 2

• Kwon SY, Na K, Han Y, Song S, Park YJ. Nicotinamide mononucleotide attenuates hepatic endoplasmic reticulum stress and modulates circadian rhythms in young mice with diet-induced obesity, Nutr Res Pract, 2025 Jul 23

• Shon J, Han Y, Park YJ. Effects of dietary fat to carbohydrate ratio on obesity risk depending on genotypes of circadian genes, Nutrients, 2022 Jan 22

• Lyu J, Lee K, Jung S, Park YJ. Associations of meal timing and sleep duration with incidence of obesity: a prospective cohort study, J Nutr Health Aging, 2024 Apr 2

3) Multi-Omics Analysis

Leveraging genomics, transcriptomics, epigenomics, and metabolomics, our lab employs integrated multi-omics approaches to identify molecular signatures underlying metabolic disease and cancer, and to discover actionable biomarkers.

Epigenomics in Cancer

Epigenetic dysregulation is a hallmark of cancer, and our lab has characterized how specific histone mutations and methyltransferase activity reshape the cancer epigenome. In collaboration with international partners, we performed genome-wide DNA methylation profiling of giant cell tumor of bone (GCTB) — a bone neoplasm driven by a recurrent H3.3-G34W histone mutation — revealing globally altered methylation landscapes, heterochromatin defects, and impaired osteogenic differentiation. Transcriptomic and proteomic analyses further showed that H3.3-G34W aligns with the RNA splicing repressor hnRNPA1L2, linking chromatin state to aberrant RNA processing in tumors.

In lung cancer, we demonstrated that inhibition of EHMT2 (G9a), a histone H3K9 methyltransferase, induces cell death in non-small cell lung cancer by altering the cholesterol biosynthesis pathway through regulation of ATF4. In ovarian cancer, we identified KDM1B (a histone demethylase) as a target of natural plant extracts (Oldenlandia diffusa, cordycepin from Cordyceps militaris) and showed that its modulation can overcome cisplatin resistance.

Epigenomics in Metabolic Disease and Aging

Our lab applies DNA methylation profiling to identify epigenetic biomarkers of metabolic disease. Using the Korean Diabetes Prevention Study (KDPS) cohort, we have identified CpG methylation changes associated with weight loss response in individuals with prediabetes, with pathway analysis highlighting dysregulated Notch signaling as a T2DM-relevant mechanism. We have also developed tissue-specific epigenetic clocks using age-associated DNA methylation patterns in mouse blood and tail, providing tools for longitudinal aging research.

At the RNA epigenomics level, we have shown that TET2, a DNA demethylase, controls early adipogenesis by inducing DDX5 (DEAD box helicase 5) through active demethylation, while the m6A RNA demethylase ALKBH5 plays a role in fine-tuning cell differentiation. These findings expand our understanding of how both DNA and RNA epigenetic modifications coordinate metabolic cell fate decisions.

Key publications:

• Lutsik P, Baude A, Mancarella D, Öz S, Kühn A, Toth R, Hey J, Toprak UH, Lim J, Nguyen VH, Jiang C, Mayakonda A, Hartmann M, Rosemann F, Breuer K, Vonficht D, Grünschläger F, Lee S, Schuhmacher MK, Kusevic D, Jauch A, Weichenhan D, Zustin J, Schlesner M, Haas S, Park JH, Park YJ, Oppermann U, Jeltsch A, Haller F, Fellenberg J, Lindroth AM, Plass C. Globally altered epigenetic landscape and delayed osteogenic differentiation in H3.3-G34W-mutant giant cell tumor of bone, Nat Commun, 2020 Oct 27

• Lee E, Park YJ, Lindroth AM. H3.3-G34W in giant cell tumor of bone functionally aligns with the exon choice repressor hnRNPA1L2, Cancer Gene Ther, 2024 May 29

• Kim H, Choi SY, Lim J, Lindroth AM, Park YJ. EHMT2 inhibition induces cell death in human non-small cell lung cancer by altering the cholesterol biosynthesis pathway, Int J Mol Sci, 2020 Feb 3

• Song S, Kim GH, Chon S, Lindroth AM, Park YJ. 718-P: DNA methylation biomarkers associated with weight loss response for individuals with prediabetes based on Korean Diabetes Prevention Study (KDPS), Diabetes, 2025 Jun 20

• Shin J, Song S, Han Y, Lyu J, Park YJ. Age-associated DNA methylation patterns in mouse blood and tail: feasibility of tissue-specific epigenetic clock development, GeroScience, 2026 Jul 9

• Cho M, Lee E, Shon J, Choi MJ, Park JH, Park YJ. Induction of DEAD box helicase 5 in early adipogenesis is regulated by Ten-eleven translocation 2, Biochim Biophys Acta Mol Cell Biol Lipids, 2020 Mar 10