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.

Základní údaje

Originální název

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

Autoři

FRÖHLICH, Jan (203 Česká republika, domácí); Niccolo LIORNI; Manuel MANGONI; Gabriela LOCHMANOVÁ (203 Česká republika, domácí); Pavlína PÍREK (203 Česká republika, domácí); Nikola KAŠTÁNKOVÁ (203 Česká republika, domácí); Pille PATA; Jan KUČERA (203 Česká republika, domácí); George N CHALDAKOV; Anton B TONCHEV; Illar PATA; Vera GORBUNOVA; Eric LEIRE; Zbyněk ZDRÁHAL (203 Česká republika, domácí); Tommaso MAZZA a Manlio VINCIGUERRA (380 Itálie, garant, domácí)

Vydání

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

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30101 Human genetics

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 4.800 v roce 2023

Organizační jednotka

Středoevropský technologický institut

DOI

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

UT WoS

001272752200001

EID Scopus

2-s2.0-85199157268

Klíčová slova anglicky

SIRT6; Epigenetics; Adipogenesis; Histones; Obesity

Štítky

14110132, CF PROT, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 3. 9. 2025 08:03, Mgr. Eva Dubská

Anotace

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.

Návaznosti

GA22-28190S, projekt VaV

Název: Komplexní charakterizace histonových epigenetických značek

Investor: Grantová agentura ČR, Komplexní charakterizace histonových epigenetických značek

90242, velká výzkumná infrastruktura

Název: CIISB III

90254, velká výzkumná infrastruktura

Název: 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 a Manlio VINCIGUERRA. Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant. CLINICAL EPIGENETICS. LONDON: BMC, 2024, roč. 16, č. 1, s. 1-17. ISSN 1868-7075. Dostupné z: 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 a Manlio VINCIGUERRA. Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant. \textit{CLINICAL EPIGENETICS}. LONDON: BMC, 2024, roč.~16, č.~1, s.~1-17. ISSN~1868-7075. Dostupné z: https://dx.doi.org/10.1186/s13148-024-01710-1.

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