KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response

Rabhi, Nabil; Denechaud, Pierre-Damien; Gromada, Xavier; Hannou, Sarah Anissa; Zhang, Hongbo; Rashid, Talha; Salas, Elisabet; Durand, Emmanuelle; Sand, Olivier; Bonnefond, Amélie; Yengo, Loïc; Chavey, Carine; Bonner, Caroline; Kerr–Conte, Julie; Abderrahmani, Amar; Auwerx, Johan; Fajas, Lluís; Froguel, Philippe; Annicotte, Jean-Sébastien

doi:10.1016/j.celrep.2016.03.079

Cited by 27 publications

(34 citation statements)

References 47 publications

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“…HUANG_FOXA2_TARGETS_UP comprises 45 genes, some of which have been suggested to be implicated in the development of diabetes, such as KAT2B and TNFAIP3. Rabhi et al found that disruption of KAT2B led to impaired insulin secretion and glucose intolerance in mice [26]. They suggested that KAT2B was a key transcriptional regulator in maintaining normal function of adaptive β cell [26].…”

Section: Discussionmentioning

confidence: 99%

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Integrating Genome-Wide Association and eQTLs Studies Identifies the Genes and Gene Sets Associated with Diabetes

Liang

Wang

et al. 2017

BioMed Research International

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Aim To identify novel candidate genes and gene sets for diabetes. Methods We performed an integrative analysis of genome-wide association studies (GWAS) and expression quantitative trait loci (eQTLs) data for diabetes. Summary data was driven from a large-scale GWAS of diabetes, totally involving 58,070 individuals. eQTLs dataset included 923,021 cis-eQTL for 14,329 genes and 4,732 trans-eQTL for 2,612 genes. Integrative analysis of GWAS and eQTLs data was conducted by summary data-based Mendelian randomization (SMR). To identify the gene sets associated with diabetes, the SMR single gene analysis results were further subjected to gene set enrichment analysis (GSEA). A total of 13,311 annotated gene sets were analyzed in this study. Results SMR analysis identified 6 genes significantly associated with fasting glucose, such as C11ORF10 (p value = 6.04 × 10−8), MRPL33 (p value = 1.24 × 10−7), and FADS1 (p value = 2.39 × 10−7). Gene set analysis identified HUANG_FOXA2_TARGETS_UP (false discovery rate = 0.047) associated with fasting glucose. Conclusion Our study provides novel clues for clarifying the genetic mechanism of diabetes. This study also illustrated the good performance of SMR approach and extended it to gene set association analysis for complex diseases.

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Section: Discussionmentioning

confidence: 99%

“…Rabhi et al found that disruption of KAT2B led to impaired insulin secretion and glucose intolerance in mice [26]. They suggested that KAT2B was a key transcriptional regulator in maintaining normal function of adaptive β cell [26]. TNFAIP3 was suggested to be associated with type 1 diabetes [27].…”

Section: Discussionmentioning

confidence: 99%

Integrating Genome-Wide Association and eQTLs Studies Identifies the Genes and Gene Sets Associated with Diabetes

Liang

Wang

et al. 2017

BioMed Research International

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“…During embryogenesis, GCN5 mRNA is already expressed at high levels by day 8, whereas KAT2b mRNA is first detected on day 12.5, suggesting that KAT2b and GCN5 play distinct roles by controlling the expression of a distinct set of genes ( 34 ). We have demonstrated that KAT2b is required for pancreatic β-cell adaptation to metabolic stress by promoting histone acetylation and gene expression of several unfolded protein response markers ( 35 ). While a β-cell-specific deletion of Kat2b in mouse has no effect under normal diet, Kat2b deficiency leads to a dramatic effect on β-cell morphology and function upon high fat feeding.…”

Section: Acetyl-coa and Histone/lysine Acetyltransferase Enzymesmentioning

confidence: 99%

“…While a β-cell-specific deletion of Kat2b in mouse has no effect under normal diet, Kat2b deficiency leads to a dramatic effect on β-cell morphology and function upon high fat feeding. KAT2b is thereby a major sensor of acetyl-CoA under hyperglycemic condition ( 35 ). Altogether, those data suggest that distinct histone acetyltransferases can sense acetyl-CoA upon different conditions and translate the appropriate cell response by activating different sets of genes.…”

Section: Acetyl-coa and Histone/lysine Acetyltransferase Enzymesmentioning

confidence: 99%

Cofactors As Metabolic Sensors Driving Cell Adaptation in Physiology and Disease

et al. 2017

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Chromatin architectures and epigenetic fingerprint regulation are fundamental for genetically determined biological processes. Chemical modifications of the chromatin template sensitize the genome to intracellular metabolism changes to set up diverse functional adaptive states. Accumulated evidence suggests that the action of epigenetic modifiers is sensitive to changes in dietary components and cellular metabolism intermediates, linking nutrition and energy metabolism to gene expression plasticity. Histone posttranslational modifications create a code that acts as a metabolic sensor, translating changes in metabolism into stable gene expression patterns. These observations support the notion that epigenetic reprograming-linked energy input is connected to the etiology of metabolic diseases and cancer. In the present review, we introduce the role of epigenetic cofactors and their relation with nutrient intake and we question the links between epigenetic regulation and the development of metabolic diseases.

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“…Further, Rabhi et al (2016) have identified a role for Lysine Acetyltransferase 2B (Kat2b) in the control of insulin secretion and pancreatic beta cell adaptation to metabolic stress through cellautonomous regulation of the UPR. This results in the induction of various ER chaperone, co-chaperone and ER-associated degradation genes after 24 h and an increase in pro-apoptotic genes (CHOP and Trib3) following 48 h of mutant insulin expression.…”

Section: Pancreatic Beta Cell Response To Er Stressmentioning

confidence: 99%

Endocrine Imbalance Associated With Proteome Changes in Diabetes

Khairallah

Farag

Johar

et al. 2017

J of Cellular Biochemistry

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The dynamics of cellular metabolism involves rapid interactions between proteins and nucleic acids, proteins and proteins, and signaling. These involve the interactions with respect to the sulfur bond, noncovalent electrostatic interactions, protein structure stabilization and protein-ligand binding, weak electrostatic interactions in proteins, oxygen radicals that initiate a change in conformation and a chain of events. We review a development in molecular medicine that is a very promising work in progress. We also review the current and future research methods involving mitochondria. Long-term effects of diabetes include glycation of proteins, for example, glycohemoglobin (HbA1c), increased risk of cardiovascular diseases, atherosclerosis, retinopathy, nephropathy, and neurological dysfunctions. Tissues are exposed to significant quantities of highly reactive chemical species including nitric oxide NO and reactive oxygen species ROS over months to years, to an extent generated by mitochondrial activities. The reactions of NO can be broadly discussed with reference to three main processes which control their fate in biological systems: (1) diffusion and intra-cellular consumption; (2) autooxidation to form nitrous anhydride N O ; and (3) reaction with superoxide O2 - to form peroxynitrite ONOO-. Reactive nitrogen species produced by macrophages and neutrophils in the interstitial space, with emphasis on NO, N O , ONOO-, and nitrogen dioxide radicals NO generate protein and DNA damage. Serum thiol (-SH) groups act as an important extracellular scavenger of peroxides and are therefore helpful in protecting the surrounding tissues. The events described here are a homeostatic endocrine imbalance that is associated with proteostasis. The advances we have seen in untangling this web of interactions are sure to continue at a breathtaking pace. J. Cell. Biochem. 118: 3569-3576, 2017. © 2017 Wiley Periodicals, Inc.

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KAT2B Is Required for Pancreatic Beta Cell Adaptation to Metabolic Stress by Controlling the Unfolded Protein Response

Cited by 27 publications

References 47 publications

Integrating Genome-Wide Association and eQTLs Studies Identifies the Genes and Gene Sets Associated with Diabetes

Integrating Genome-Wide Association and eQTLs Studies Identifies the Genes and Gene Sets Associated with Diabetes

Cofactors As Metabolic Sensors Driving Cell Adaptation in Physiology and Disease

Endocrine Imbalance Associated With Proteome Changes in Diabetes

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