LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation

Kotaro Anan, Shinjiro Hino, Noriaki Shimizu, Akihisa Sakamoto, Katsuya Nagaoka, Ryuta Takase, Kensaku Kohrogi, Hirotaka Araki, Yuko Hino, Shingo Usuki, Shinya Oki, Hirotoshi Tanaka, Kimitoshi Nakamura, Fumio Endo, Mitsuyoshi Nakao

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The metabolic properties of cells are formed under the influence of environmental factors such as nutrients and hormones. Although such a metabolic program is likely initiated through epigenetic mechanisms, the direct links between metabolic cues and activities of chromatin modifiers remain largely unknown. In this study, we show that lysine-specific demethylase-1 (LSD1) controls the metabolic program in myogenic differentiation, under the action of catabolic hormone, glucocorticoids. By using tran-scriptomic and epigenomic approaches, we revealed that LSD1 bound to oxidative metabolism and slow-twitch myosin genes, and repressed their expression. Consistent with this, loss of LSD1 activity during differentiation enhanced the oxidative capacity of myotubes. By testing the effects of various hormones, we found that LSD1 levels were decreased by treatment with the glucocorticoid dexamethasone (Dex) in cultured myoblasts and in skeletal muscle from mice. Mechanistically, glucocorticoid signaling induced expression of a ubiquitin E3 ligase, JADE-2, which was responsible for proteasomal degradation of LSD1. Consequently, in differentiating myoblasts, chemical inhibition of LSD1, in combination with Dex treatment, synergistically de-repressed oxidative metabolism genes, concomitant with increased histone H3 lysine 4 methylation at these loci. These findings demonstrated that LSD1 serves as an epigenetic regulator linking glucocorticoid action to metabolic programming during myogenic differentiation.

Original languageEnglish
Pages (from-to)5441-5454
Number of pages14
JournalNucleic acids research
Volume46
Issue number11
DOIs
Publication statusPublished - Jan 1 2018

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Glucocorticoids
Lysine
Epigenomics
Myoblasts
Hormones
Dexamethasone
Ubiquitin-Protein Ligases
Skeletal Muscle Fibers
Myosins
Histones
Methylation
Genes
Chromatin
Cues
Skeletal Muscle
Food

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Anan, K., Hino, S., Shimizu, N., Sakamoto, A., Nagaoka, K., Takase, R., ... Nakao, M. (2018). LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation. Nucleic acids research, 46(11), 5441-5454. https://doi.org/10.1093/nar/gky234

LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation. / Anan, Kotaro; Hino, Shinjiro; Shimizu, Noriaki; Sakamoto, Akihisa; Nagaoka, Katsuya; Takase, Ryuta; Kohrogi, Kensaku; Araki, Hirotaka; Hino, Yuko; Usuki, Shingo; Oki, Shinya; Tanaka, Hirotoshi; Nakamura, Kimitoshi; Endo, Fumio; Nakao, Mitsuyoshi.

In: Nucleic acids research, Vol. 46, No. 11, 01.01.2018, p. 5441-5454.

Research output: Contribution to journalArticle

Anan, K, Hino, S, Shimizu, N, Sakamoto, A, Nagaoka, K, Takase, R, Kohrogi, K, Araki, H, Hino, Y, Usuki, S, Oki, S, Tanaka, H, Nakamura, K, Endo, F & Nakao, M 2018, 'LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation', Nucleic acids research, vol. 46, no. 11, pp. 5441-5454. https://doi.org/10.1093/nar/gky234
Anan K, Hino S, Shimizu N, Sakamoto A, Nagaoka K, Takase R et al. LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation. Nucleic acids research. 2018 Jan 1;46(11):5441-5454. https://doi.org/10.1093/nar/gky234
Anan, Kotaro ; Hino, Shinjiro ; Shimizu, Noriaki ; Sakamoto, Akihisa ; Nagaoka, Katsuya ; Takase, Ryuta ; Kohrogi, Kensaku ; Araki, Hirotaka ; Hino, Yuko ; Usuki, Shingo ; Oki, Shinya ; Tanaka, Hirotoshi ; Nakamura, Kimitoshi ; Endo, Fumio ; Nakao, Mitsuyoshi. / LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation. In: Nucleic acids research. 2018 ; Vol. 46, No. 11. pp. 5441-5454.
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