Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects

Cajsa Davegårdh; Christa Broholm; Alexander Perfilyev; Tora Henriksen; Sonia García-Calzón; Lone Peijs; Ninna Schiøler Hansen; Petr Volkov; Rasmus Kjøbsted; Jørgen Wojtaszewski; Maria Pedersen; Bente Klarlund Pedersen; Dov B Ballak; Charles A Dinarello; Bas Heinhuis; Leo A B Joosten; Emma Nilsson; Allan Vaag; Camilla Scheele; Charlotte Ling

doi:10.1186/s12916-017-0792-x

Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects

Cajsa Davegårdh, Christa Broholm, Alexander Perfilyev, Tora Henriksen, Sonia García-Calzón, Lone Peijs, Ninna Schiøler Hansen, Petr Volkov, Rasmus Kjøbsted, Jørgen Wojtaszewski, Maria Pedersen, Bente Klarlund Pedersen, Dov B Ballak, Charles A Dinarello, Bas Heinhuis, Leo A B Joosten, Emma Nilsson, Allan Vaag, Camilla Scheele, Charlotte Ling

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Abstract

BACKGROUND: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects.

METHODS: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model.

RESULTS: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects.

CONCLUSIONS: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.

Originalsprog	Engelsk
Artikelnummer	39
Tidsskrift	BMC Medicine
Vol/bind	15
Antal sider	27
ISSN	1741-7015
DOI	https://doi.org/10.1186/s12916-017-0792-x
Status	Udgivet - 22 feb. 2017

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10.1186/s12916-017-0792-xLicens: CC BY

Davegårdh et al_BMC Medicine_2017_Vol 15_39Forlagets udgivne version, 1,63 MBLicens: CC BY

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Davegårdh, C., Broholm, C., Perfilyev, A., Henriksen, T., García-Calzón, S., Peijs, L., Hansen, N. S., Volkov, P., Kjøbsted, R., Wojtaszewski, J., Pedersen, M., Pedersen, B. K., Ballak, D. B., Dinarello, C. A., Heinhuis, B., Joosten, L. A. B., Nilsson, E., Vaag, A., Scheele, C., & Ling, C. (2017). Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects. BMC Medicine, 15, Artikel 39. https://doi.org/10.1186/s12916-017-0792-x

Davegårdh, C, Broholm, C, Perfilyev, A, Henriksen, T, García-Calzón, S, Peijs, L, Hansen, NS, Volkov, P, Kjøbsted, R , Wojtaszewski, J, Pedersen, M, Pedersen, BK, Ballak, DB, Dinarello, CA, Heinhuis, B, Joosten, LAB, Nilsson, E, Vaag, A , Scheele, C & Ling, C 2017, 'Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects', BMC Medicine, bind 15, 39. https://doi.org/10.1186/s12916-017-0792-x

@article{08bfae72a6664c51955e546100916b86,

title = "Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects",

abstract = "BACKGROUND: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects.METHODS: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model.RESULTS: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects.CONCLUSIONS: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.",

keywords = "DNA methylation, Myogenesis, Obesity, IL-32, Epigenetics, ARPP21, TGF- 3, PSG, CGB, MT, Insulin resistance",

author = "Cajsa Daveg{\aa}rdh and Christa Broholm and Alexander Perfilyev and Tora Henriksen and Sonia Garc{\'i}a-Calz{\'o}n and Lone Peijs and Hansen, {Ninna Schi{\o}ler} and Petr Volkov and Rasmus Kj{\o}bsted and J{\o}rgen Wojtaszewski and Maria Pedersen and Pedersen, {Bente Klarlund} and Ballak, {Dov B} and Dinarello, {Charles A} and Bas Heinhuis and Joosten, {Leo A B} and Emma Nilsson and Allan Vaag and Camilla Scheele and Charlotte Ling",

note = "CURIS 2017 NEXS 077",

year = "2017",

month = feb,

day = "22",

doi = "10.1186/s12916-017-0792-x",

language = "English",

volume = "15",

journal = "BMC Medicine",

issn = "1741-7015",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects

AU - Davegårdh, Cajsa

AU - Broholm, Christa

AU - Perfilyev, Alexander

AU - Henriksen, Tora

AU - García-Calzón, Sonia

AU - Peijs, Lone

AU - Hansen, Ninna Schiøler

AU - Volkov, Petr

AU - Kjøbsted, Rasmus

AU - Wojtaszewski, Jørgen

AU - Pedersen, Maria

AU - Pedersen, Bente Klarlund

AU - Ballak, Dov B

AU - Dinarello, Charles A

AU - Heinhuis, Bas

AU - Joosten, Leo A B

AU - Nilsson, Emma

AU - Vaag, Allan

AU - Scheele, Camilla

AU - Ling, Charlotte

N1 - CURIS 2017 NEXS 077

PY - 2017/2/22

Y1 - 2017/2/22

N2 - BACKGROUND: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects.METHODS: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model.RESULTS: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects.CONCLUSIONS: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.

AB - BACKGROUND: Human skeletal muscle stem cells are important for muscle regeneration. However, the combined genome-wide DNA methylation and expression changes taking place during adult myogenesis have not been described in detail and novel myogenic factors may be discovered. Additionally, obesity is associated with low relative muscle mass and diminished metabolism. Epigenetic alterations taking place during myogenesis might contribute to these defects.METHODS: We used Infinium HumanMethylation450 BeadChip Kit (Illumina) and HumanHT-12 Expression BeadChip (Illumina) to analyze genome-wide DNA methylation and transcription before versus after differentiation of primary human myoblasts from 14 non-obese and 14 obese individuals. Functional follow-up experiments were performed using siRNA mediated gene silencing in primary human myoblasts and a transgenic mouse model.RESULTS: We observed genome-wide changes in DNA methylation and expression patterns during differentiation of primary human muscle stem cells (myoblasts). We identified epigenetic and transcriptional changes of myogenic transcription factors (MYOD1, MYOG, MYF5, MYF6, PAX7, MEF2A, MEF2C, and MEF2D), cell cycle regulators, metabolic enzymes and genes previously not linked to myogenesis, including IL32, metallothioneins, and pregnancy-specific beta-1-glycoproteins. Functional studies demonstrated IL-32 as a novel target that regulates human myogenesis, insulin sensitivity and ATP levels in muscle cells. Furthermore, IL32 transgenic mice had reduced insulin response and muscle weight. Remarkably, approximately 3.7 times more methylation changes (147,161 versus 39,572) were observed during differentiation of myoblasts from obese versus non-obese subjects. In accordance, DNMT1 expression increased during myogenesis only in obese subjects. Interestingly, numerous genes implicated in metabolic diseases and epigenetic regulation showed differential methylation and expression during differentiation only in obese subjects.CONCLUSIONS: Our study identifies IL-32 as a novel myogenic regulator, provides a comprehensive map of the dynamic epigenome during differentiation of human muscle stem cells and reveals abnormal epigenetic changes in obesity.

KW - DNA methylation

KW - Myogenesis

KW - Obesity

KW - IL-32

KW - Epigenetics

KW - ARPP21

KW - TGF- 3

KW - PSG

KW - CGB

KW - MT

KW - Insulin resistance

U2 - 10.1186/s12916-017-0792-x

DO - 10.1186/s12916-017-0792-x

M3 - Journal article

C2 - 28222718

SN - 1741-7015

VL - 15

JO - BMC Medicine

JF - BMC Medicine

M1 - 39

ER -

Abnormal epigenetic changes during differentiation of human skeletal muscle stem cells from obese subjects

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