A UBE3A-UTX Proteostasis-Epigenetic Axis Governs Hypothalamic Energy Homeostasis.
Overview
- College of Pharmacy, Seoul National University, Seoul, Republic of Korea
- Department of Biopharmaceutical Sciences, Cheongju University, Cheongju, Republic of Korea
- Korea Mouse Phenotyping Center, Seoul National University, Seoul, Republic of Korea
- Research Institute of Pharmaceutical Sciences and Natural Products Research Institute, Seoul National University, Seoul, Republic of Korea
- Seoul National University Energy Initiative, Seoul National University, Seoul, Republic of Korea
Abstract
Energy homeostasis requires integration of metabolic and stress signals within hypothalamic circuits, yet the role of neuronal proteostasis remains unclear. Ubiquitin protein ligase E3A (UBE3A) regulates the stability of lysine demethylase 6A (KDM6A), also known as ubiquitously transcribed tetratricopeptide repeat containing, X chromosome (UTX). Hypothalamic neuronal deletion of Ube3a results in hyperphagia, obesity, hyperleptinemia, and impaired glucose homeostasis under high‐fat diet conditions; selective deletion in agouti‐related peptide (AgRP) neurons is sufficient to recapitulate these phenotypes. UBE3A promotes UTX degradation, whereas UBE3A loss stabilizes UTX and decreases repressive histone H3 lysine 27 trimethylation (H3K27me3). Integrated transcriptomic and epigenomic analyses implicate UTX and activating transcription factor 4 (ATF4) in altered endoplasmic reticulum (ER) stress‐responsive transcriptional programs, although their causal contribution to the metabolic phenotype remains to be established. Treatment with GSK‐J4, an inhibitor of KDM6‐family demethylases, increases hypothalamic H3K27me3 levels and improves metabolic outcomes in Ube3a‐deficient mice, although the specific contribution of hypothalamic UTX inhibition to these effects remains to be established. These findings support a link between neuronal proteostasis, chromatin regulation, and systemic metabolic homeostasis and warrant further investigation of the relevance of UTX‐associated pathways to metabolic dysfunction in a subset of individuals with Angelman syndrome.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE104709, at NCBI GEO; found in the text, “UBE3A Selectively Regulates the Hypothalamic…”
Data Availability Statement
The data that support the findings of this study are available in the supplementary material of this article.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 31 October 2026: the first record
Recorded: type, language, journal, pages, dates, 8 authors, 5 keywords, 3 funders, 60 references.
Cite
This paper
Lee, J., Yoo, J., Kim, Y. A., Wei, Z., Lee, Y., Shon, W., Seong, J. K., & Lee, S. (2026). A UBE3A-UTX Proteostasis-Epigenetic Axis Governs Hypothalamic Energy Homeostasis. Advanced science (Weinheim, Baden-Wurttemberg, Germany), e78567. https://
BibTeX
@article{lee2026ube3a,
author = {Lee, Junekyoung and Yoo, Jaeyoung and Kim, Young A and Wei, Zhuodu and Lee, Yunseo and Shon, Woo‐Jeong and Seong, Je Kyung and Lee, Seunghee},
title = {{A UBE3A-UTX Proteostasis-Epigenetic Axis Governs Hypothalamic Energy Homeostasis}},
journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
year = {2026},
month = oct,
pages = {e78567},
publisher = {Wiley},
issn = {2198-3844},
doi = {10.1002/
url = {https://
pmid = {42958748},
pmcid = {PMC13720268}
}
RIS
TY - JOUR
AU - Lee, Junekyoung
AU - Yoo, Jaeyoung
AU - Kim, Young A
AU - Wei, Zhuodu
AU - Lee, Yunseo
AU - Shon, Woo‐Jeong
AU - Seong, Je Kyung
AU - Lee, Seunghee
TI - A UBE3A-UTX Proteostasis-Epigenetic Axis Governs Hypothalamic Energy Homeostasis
T2 - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
J2 - Adv Sci (Weinh)
PY - 2026
DA - 2026/
SP - e78567
SN - 2198-3844
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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