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SIRT6 regulates glucose metabolism and glutamatergic synapse in the mouse retina

ABSTRACT: Microarray analysis on total retinal RNA from 15 day old Sirt6 wild-type (WT) and knock-out (KO) mice. The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin.

ORGANISM(S): Mus musculus

PROVIDER: GSE56563 | GEO | 2014/07/30

SECONDARY ACCESSION(S): PRJNA243911

REPOSITORIES: GEO

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SIRT6 regulates glucose metabolism and glutamatergic synapse in the mouse retina

Project description:Microarray analysis on total retinal RNA from 15 day old Sirt6 wild-type (WT) and knock-out (KO) mice. The retina is one of the major energy consuming tissues within the body. In this context, synaptic transmission between light-excited rod photoreceptors and downstream ON-bipolar neurons is a highly demanding energy consuming process. Sirtuin 6 (SIRT6), a NAD-dependent deacylase, plays a key role in regulating glucose metabolism. In this study, we demonstrate that SIRT6 is highly expressed in the retina, controlling levels of histone H3K9 and H3K56 acetylation. Notably, despite apparent normal histology, SIRT6 deficiency caused major retinal transmission defects concomitant to changes in expression of glycolytic genes and glutamate receptors, as well as elevated levels of apoptosis in inner retina cells. Our results identify SIRT6 as a critical modulator of retinal function, likely through its effects on chromatin. Microarray analysis of total retinal RNA from 15 day old Sirt6 wild-type (WT) and knock-out (KO) mice with 3 replicates in each condition using the Affymetrix Mouse Gene 2.1 ST array (transcript (gene) version).

2014-07-30 | E-GEOD-56563 | biostudies-arrayexpress

Restoration of energy homeostasis by SIRT6 extends healthy lifespan

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2021-03-11 | PXD021447 | Pride

SIRT6 haploinsufficiency induces BRAFV600E melanoma cell resistance to MAPK inhibitors via IGF signaling

Project description:Through integrated transcriptomic, epigenomic and proteomic analyses, we identified IGFBP2, an insulin growth factor (IGF) binding protein, as a direct SIRT6 target gene. We further show that SIRT6 haploinsufficiency, but not complete knock out of SIRT6 promotes IGFBP2 expression via increased H3K56 acetylation at the IGFBP2 locus allowing melanoma cell survival in the presence of MAPK signaling inhibitors (MAPKi).

2018-08-18 | GSE102813 | GEO

Genome-wide DNA accessibility maps after Sirt6 inactivation in muscle stem cells [ATAC-seq]

Project description:Sirt6, the NAD+-dependent deacetylase, has been described to deacetylate H3K9, H3K18, and H3K56. However, analysis of the acetylation status revealed that loss of Sirt6 caused a massive increase of histone H3K56ac levels but no detectable change of histone H3K9ac and H3K18ac, indicating that SIRT6 is the dominant deacetylase for H3K56ac in muscle stem cells (MuSCs). Further, we investigate genome transposase-accessible chromatin in the absence of Sirt6 in MuSCs using high throughput sequencing (ATAC-seq).

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Genome-wide H3K56ac profiling after Sirt6 knockdown in mESCs [ChIP-seq]

Project description:Sirt6, the NAD+-dependent deacetylase, has been described to deacetylate H3K9, H3K18, and H3K56. However, analysis of the acetylation status revealed that loss of Sirt6 caused a massive increase of histone H3K56ac levels but no detectable change of histone H3K9ac and H3K18ac, indicating that SIRT6 is the dominant deacetylase for H3K56ac in muscle stem cells (MuSCs). Further, we investigate genome-wide H3K56ac profiling in the absence of Sirt6 in MuSCs and mouse embryonic stem cells (mESCs) using high throughput sequencing (ChIP-seq).

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Genome-wide H3K56ac profiling after Sirt6 inactivation in MuSCs [ChIP-seq]

Project description:Sirt6, the NAD+-dependent deacetylase, has been described to deacetylate H3K9, H3K18, and H3K56. However, analysis of the acetylation status revealed that loss of Sirt6 caused a massive increase of histone H3K56ac levels but no detectable change of histone H3K9ac and H3K18ac, indicating that SIRT6 is the dominant deacetylase for H3K56ac in muscle stem cells (MuSCs). Further, we investigate genome-wide H3K56ac profiling in the absence of Sirt6 in MuSCs and mouse embryonic stem cells (mESCs) using high throughput sequencing (ChIP-seq).

2022-05-13 | GSE168330 | GEO

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A

Project description:Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in the regulation of aging and metabolism. Targeted sequencing identified a SIRT6 allele containing two linked substitutions (N308K/A313S) as enriched in Ashkenazi Jewish (AJ) centenarians as compared to AJ control individuals. Characterization of this SIRT6 (centSIRT6) allele demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double strand break repair, and more robust cancer cell killing compared to the wild type. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

2022-10-21 | PXD035689 | Pride

Gene expression profiling of shRNA transduced rat hippocampal neurons

Project description:Sirtuin 6 (SIRT6), a member of the sirtuin family, acts as nicotinamide adenine dinucleotide-dependent protein deacetylase, mono-adenosine diphosphate-ribosyltransferase, and fatty acid deacylase and plays critical roles in inflammation, aging, glycolysis, and DNA repair. Accumulating evidence has suggested that SIRT6 is involved in brain functions such as neuronal differentiation, neurogenesis, and learning and memory. However, the precise molecular roles of SIRT6 during neuronal circuit formation are not well understood. In this study, we attemped to elucidate the molecular roles of SIRT6 on neurite development using a primary culture of hippocampal neurons. We observed that SIRT6 was abundantly localized in the nucleus, and its expression was markedly increased during neurite outgrowth and synaptogenesis. Using shRNA-mediated SIRT6 knockdown, we showed that the dendritic length and number of dendrite branches were significantly reduced in SIRT6 knockdown neurons. Microarray and subsequent gene ontology analysis revealed that reducing SIRT6 caused the downregulation of immediate early genes (IEGs) and alteration of several biological processes including MAPK (ERK1/2) signaling. We found that nuclear accumulation of phosphorylated ERK1/2 was significantly reduced in SIRT6 knockdown neurons. Overexpression of SIRT6 promoted dendritic length and branching, but the mutants lacking deacetylase activity had no significant effect on the dendritic morphology. Collectively, the presented findings reveal a role of SIRT6 in dendrite morphogenesis and suggest that SIRT6 may act as an important regulator of the ERK1/2 signaling pathway that mediates IEG expression, which leads to dendritic development.

2021-02-09 | GSE153304 | GEO

Rat retina and optic nerve LC-MS/MS

Project description:Various retinal disorder such as glaucomatous, retinal ischemia reperfusion, and traumatic optic neuropathy, are involved in the pathogenesis of neurodegeneration via glutamate exicitotoxicity. However, the proteomic characteristics and modulation of the neural-microenvironment with NMDA-induced neurodegeneration in retina and optic nerve remain partly understood. We established a protein sketch of NMDA-induced injury by comparing the proteomes of the PBS-operated, NMDA-operated and control groups. We carried out mass spectrometry-based label-free quantitative proteomics to investigate the exicitotoxic neurodegeneration mechanisms and identify key proteins that regulated neural cell death related signaling pathway in retina and optic nerve spatially. Using LC-MS/MS proteomics analysis, in total, we identified 3532 proteins in retina, 2593 proteins in optic nerve. According to Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), the protein changes and energy metabolism in retina and optic nerve tissue were comprehensively evaluated.

2021-12-30 | PXD022466 | Pride

Rat retina and optic nerve LC-MS/MS

2021-12-30 | PXD022729 | Pride

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