Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Gabriel, Brendan M.; Altıntaş, Ali; Smith, Jonathon A. B.; Puig, Laura; Zhang, Xiping; Basse, Astrid L.; Laker, Rhianna C.; Gao, Hui; Liu, Zhengye; Dollet, Lucile; Treebak, Jonas T.; Zorzano, António; Huo, Zhiguang; Rydén, Mikael; Lanner, Johanna T.; Esser, Karyn A.; Barrès, Romain; Pillon, Nicolas; Krook, Anna; Zierath, Juleen R.

doi:10.1126/sciadv.abi9654

Cited by 71 publications

(55 citation statements)

References 76 publications

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“…Microarray data and sample information from two gene expression profile datasets (GSE29221 and GSE182120) were downloaded from the GEO ( Jain et al, 2013 ; Gabriel et al, 2021 ). GSE29221 ( Jain et al, 2013 ) was based on the GPL6947 platform Illumina HumanHT-12 V3.0 expression BeadChip ( Homo sapiens ).…”

Section: Methodsmentioning

confidence: 99%

“…For the GSE29221 dataset, 48803 probe IDs were converted to 25159 gene symbols according to platform annotation files. GSE182120 ( Gabriel et al, 2021 ) was obtained using the GPL17586 platform [HTA-2_0] Affymetrix Human Transcriptome Array 2.0. It also contained data from 49 human skeletal muscle samples, of which 25 were from T2D patients and 24 were from patients without diabetes.…”

Section: Methodsmentioning

confidence: 99%

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Comprehensive analysis of key m5C modification-related genes in type 2 diabetes

Song

Jiang

et al. 2022

Front. Genet.

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Background: 5-methylcytosine (m5C) RNA methylation plays a significant role in several human diseases. However, the functional role of m5C in type 2 diabetes (T2D) remains unclear.Methods: The merged gene expression profiles from two Gene Expression Omnibus (GEO) datasets were used to identify m5C-related genes and T2D-related differentially expressed genes (DEGs). Least-absolute shrinkage and selection operator (LASSO) regression analysis was performed to identify optimal predictors of T2D. After LASSO regression, we constructed a diagnostic model and validated its accuracy. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to confirm the biological functions of DEGs. Gene Set Enrichment Analysis (GSEA) was used to determine the functional enrichment of molecular subtypes. Weighted gene co-expression network analysis (WGCNA) was used to select the module that correlated with the most pyroptosis-related genes. Protein-protein interaction (PPI) network was established using the STRING database, and hub genes were identified using Cytoscape software. The competitive endogenous RNA (ceRNA) interaction network of the hub genes was obtained. The CIBERSORT algorithm was applied to analyze the interactions between hub gene expression and immune infiltration.Results: m5C-related genes were significantly differentially expressed in T2D and correlated with most T2D-related DEGs. LASSO regression showed that ZBTB4 could be a predictive gene for T2D. GO, KEGG, and GSEA indicated that the enriched modules and pathways were closely related to metabolism-related biological processes and cell death. The top five genes were identified as hub genes in the PPI network. In addition, a ceRNA interaction network of hub genes was obtained. Moreover, the expression levels of the hub genes were significantly correlated with the abundance of various immune cells.Conclusion: Our findings may provide insights into the molecular mechanisms underlying T2D based on its pathophysiology and suggest potential biomarkers and therapeutic targets for T2D.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Comprehensive analysis of key m5C modification-related genes in type 2 diabetes

Song

Jiang

et al. 2022

Front. Genet.

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“…RNA sequencing from myotube cultures was performed as described previously [57]. Briefly, RNA was extracted with Trizol Reagent and miRNAeasy kit (Qiagen; Cat #217004) and processed using the Illumina TruSeq Stranded Total RNA with Ribo-Zero Gold protocol (Illumina).…”

Section: Methodsmentioning

confidence: 99%

Saturated Fat Impairs Circadian Transcriptomics through Histone Modification of Enhancers

Puig

Altintas

Casani

et al. 2021

Preprint

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Aims/hypothesis: Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid-overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenetic mechanisms. Methods: We determined the effect of the saturated fatty acid palmitate on circadian transcriptomics and examined the impact on histone H3 lysine K27 acetylation (H3K27ac) and the regulation of circadian rhythms in primary human skeletal muscle myotubes. Total H3 abundance and histone H3K27ac was assessed in vastus lateralis muscle biopsies from obese and normal weight men. Results: Palmitate disrupted transcriptomic rhythmicity in myotubes. Genes that lost or gained rhythmicity after palmitate treatment were involved in metabolic processes, protein translation and transport, and transcriptional regulation. Histone H3K27ac, a marker of active gene enhancers, was modified by palmitate treatment in myotubes, but not in skeletal muscle from men with obesity. Conclusion/interpretation: Palmitate disrupts transcriptomic rhythmicity and modifies histone H3K27ac in circadian manner, suggesting acute lipid-overload alters the epigenetic state of skeletal muscle. Our results indicate that dietary saturated fatty acids impart post-transcriptional modifications to histone proteins and regulate circadian transcriptomics.

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“…RNA extraction and RNA sequencing RNA sequencing from myotube cultures was performed as described (Gabriel et al, 2021). Briefly, RNA was extracted with TRIzol Reagent and miRNeasy kit (Cat #217004; Qiagen) and processed using the Illumina TruSeq Stranded Total RNA with Ribo-Zero Gold protocol (Illumina).…”

Section: Immunoblot Analysismentioning

confidence: 99%

Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers

et al. 2022

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Obesity and elevated circulating lipids may impair metabolism by disrupting the molecular circadian clock. We tested the hypothesis that lipid overload may interact with the circadian clock and alter the rhythmicity of gene expression through epigenomic mechanisms in skeletal muscle. Palmitate reprogrammed the circadian transcriptome in myotubes without altering the rhythmic mRNA expression of core clock genes. Genes with enhanced cycling in response to palmitate were associated with post-translational modification of histones. The cycling of histone 3 lysine 27 acetylation (H3K27ac), a marker of active gene enhancers, was modified by palmitate treatment. Chromatin immunoprecipitation and sequencing confirmed that palmitate exposure altered the cycling of DNA regions associated with H3K27ac. The overlap between mRNA and DNA regions associated with H3K27ac and the pharmacological inhibition of histone acetyltransferases revealed novel cycling genes associated with lipid exposure of primary human myotubes. Palmitate exposure disrupts transcriptomic rhythmicity and modifies enhancers through changes in histone H3K27 acetylation in a circadian manner. Thus, histone acetylation is responsive to lipid overload and may redirect the circadian chromatin landscape, leading to the reprogramming of circadian genes and pathways involved in lipid biosynthesis in skeletal muscle.

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Disrupted circadian oscillations in type 2 diabetes are linked to altered rhythmic mitochondrial metabolism in skeletal muscle

Abstract: Disturbances in daily rhythms of mitochondrial activity may contribute to skeletal muscle insulin resistance in type 2 diabetes.

Cited by 71 publications

References 76 publications

Comprehensive analysis of key m5C modification-related genes in type 2 diabetes

Comprehensive analysis of key m5C modification-related genes in type 2 diabetes

Saturated Fat Impairs Circadian Transcriptomics through Histone Modification of Enhancers

Palmitate impairs circadian transcriptomics in muscle cells through histone modification of enhancers

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