Epigenetic and transcriptional control of adipocyte function by
centenarian-associated SIRT6 N308K/A313S mutant

J 2024

Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant

FRÖHLICH, Jan, Niccolo LIORNI, Manuel MANGONI, Gabriela LOCHMANOVÁ, Pavlína PÍREK et. al.

Basic information

Original name

Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant

Authors

Edition

CLINICAL EPIGENETICS, LONDON, BMC, 2024, 1868-7075

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.700 in 2022

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1186/s13148-024-01710-1

UT WoS

001272752200001

Keywords in English

SIRT6; Epigenetics; Adipogenesis; Histones; Obesity

Abstract

V originále

BackgroundObesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level.MethodsWe analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches.ResultsOverexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner.ConclusionsSIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.

Links

GA22-28190S, research and development project

Name: Komplexní charakterizace histonových epigenetických značek

Investor: Czech Science Foundation, Comprehensive characterization of histone epigenetic marks

LM2023042, research and development project

Name: Česká infrastruktura pro integrativní strukturní biologii

Investor: Ministry of Education, Youth and Sports of the CR, CIISB - Czech Infrastructure for Integrative Structural Biology

90254, large research infrastructures

Name: e-INFRA CZ II

Citovat

FRÖHLICH, Jan, Niccolo LIORNI, Manuel MANGONI, Gabriela LOCHMANOVÁ, Pavlína PÍREK, Nikola KAŠTÁNKOVÁ, Pille PATA, Jan KUČERA, George N CHALDAKOV, Anton B TONCHEV, Illar PATA, Vera GORBUNOVA, Eric LEIRE, Zbyněk ZDRÁHAL, Tommaso MAZZA and Manlio VINCIGUERRA. Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant. CLINICAL EPIGENETICS. LONDON: BMC, 2024, vol. 16, No 1, p. 1-17. ISSN 1868-7075. Available from: https://dx.doi.org/10.1186/s13148-024-01710-1.

@article{2421649,
   author = {Fröhlich, Jan and Liorni, Niccolo and Mangoni, Manuel and Lochmanová, Gabriela and Pírek, Pavlína and Kaštánková, Nikola and Pata, Pille and Kučera, Jan and Chaldakov, George N and Tonchev, Anton B and Pata, Illar and Gorbunova, Vera and Leire, Eric and Zdráhal, Zbyněk and Mazza, Tommaso and Vinciguerra, Manlio},
   article_location = {LONDON},
   article_number = {1},
   doi = {http://dx.doi.org/10.1186/s13148-024-01710-1},
   keywords = {SIRT6; Epigenetics; Adipogenesis; Histones; Obesity},
   language = {eng},
   issn = {1868-7075},
   journal = {CLINICAL EPIGENETICS},
   title = {Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant},
   url = {https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01710-1},
   volume = {16},
   year = {2024}
}

TY  - JOUR
ID  - 2421649
AU  - Fröhlich, Jan - Liorni, Niccolo - Mangoni, Manuel - Lochmanová, Gabriela - Pírek, Pavlína - Kaštánková, Nikola - Pata, Pille - Kučera, Jan - Chaldakov, George N - Tonchev, Anton B - Pata, Illar - Gorbunova, Vera - Leire, Eric - Zdráhal, Zbyněk - Mazza, Tommaso - Vinciguerra, Manlio
PY  - 2024
TI  - Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant
JF  - CLINICAL EPIGENETICS
VL  - 16
IS  - 1
SP  - 1-17
EP  - 1-17
PB  - BMC
SN  - 18687075
KW  - SIRT6
KW  - Epigenetics
KW  - Adipogenesis
KW  - Histones
KW  - Obesity
UR  - https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/s13148-024-01710-1
N2  - BackgroundObesity is a major health burden. Preadipocytes proliferate and differentiate in mature adipocytes in the adipogenic process, which could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a stress-responsive protein deacetylase and mono-ADP ribosyltransferase enzyme, blocks adipogenesis. Mutants of SIRT6 (N308K/A313S) were recently linked to the in the long lifespan Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level.MethodsWe analyzed the role of SIRT6 wild-type (WT) or SIRT6 centenarian-associated mutant (N308K/A313S) overexpression in adipogenesis, by creating stably transduced preadipocyte cell lines using lentivirus on the 3T3-L1 model. Histone post-translational modifications (PTM: acetylation, methylation) and transcriptomic changes were analyzed by mass spectrometry (LC-MS/MS) and RNA-Seq, respectively, in 3T3-L1 adipocytes. In addition, the adipogenic process and related signaling pathways were investigated by bioinformatics and biochemical approaches.ResultsOverexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner.ConclusionsSIRT6 N308K/A313S overexpression in mature adipocytes ameliorated glucose sensitivity and impacted sympathetic innervation signaling. These findings highlight the importance of targeting SIRT6 enzymatic activities to regulate the co-morbidities associated with obesity.
ER  -

FRÖHLICH, Jan, Niccolo LIORNI, Manuel MANGONI, Gabriela LOCHMANOVÁ, Pavlína PÍREK, Nikola KAŠTÁNKOVÁ, Pille PATA, Jan KUČERA, George N CHALDAKOV, Anton B TONCHEV, Illar PATA, Vera GORBUNOVA, Eric LEIRE, Zbyněk ZDRÁHAL, Tommaso MAZZA and Manlio VINCIGUERRA. Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant. \textit{CLINICAL EPIGENETICS}. LONDON: BMC, 2024, vol.~16, No~1, p.~1-17. ISSN~1868-7075. Available from: https://dx.doi.org/10.1186/s13148-024-01710-1.

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