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Genome-wide maps of histone H3K9/K14 acetylation state in HeLa cells control (Mock) or silenced for Gb3 globoside synthase (Gb3S_KD) or silenced for the epigenetic modulator AUTS2 (AUTS2_KD)

ABSTRACT: Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo to ganglio-series glycosphingolipids production. We discovered that globo-series glycosphingolipids repress the epigenetic regulator of neuronal genes expression AUTS2. AUTS2 in turn, binds and activates the promoter of the first and rate limiting ganglioside producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural genes expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology. We report Gb3 globoside suppresses the expression of the epigenetic modulator AUTS2. The silencing of Gb3 synthase in HeLa cells induces the thepletion of Gb3 globoside, consequentially promoting AUTS2 expression. AUTS2 in turn, binds and activates the promoter of the target genes promoting local histone hyperacetylation and gene expression. Thus, the globo-series glycosphingolipids, by counteracting the expression of AUTS2, decrease histone acetylation at neuronal gene promoters repressing their transcription in HeLa cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE107044 | GEO | 2017/12/22

SECONDARY ACCESSION(S): PRJNA418910

REPOSITORIES: GEO

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Genome-wide maps of histone H3K9/K14 acetylation state in HeLa cells control (Mock) or silenced for Gb3 globoside synthase (Gb3S_KD) or silenced for the epigenetic modulator AUTS2 (AUTS2_KD)

Project description:Genome-wide maps of histone H3K9/K14 acetylation state in HeLa cells control (Mock) or silenced for Gb3 globoside synthase (Gb3S_KD) or silenced for the epigenetic modulator AUTS2 (AUTS2_KD)

| PRJNA418910 | ENA

Mitochondrial stress in GLA mutants Zebrafish is independent of globotriaosylceramide accumulation

Project description:Fabry disease (FD) is a hereditary lysosomal storage disorder caused by mutations in GLA gene resulting in reduction or lack of α-galactosidase A activity. In humans, enzymatic deficiency leads to accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in lysosomes. Current therapies focus on reversing Gb3 accumulation but fail to restore altered cellular signaling in the long run. Zebrafish (ZF) lacks Alpha 1,4-Galactosyltransferase (A4GALT) gene and cannot synthesize Gb3 or lysoGb3. We used previously generated GLA-mutant ZF model to investigate Gb3-accumulation-independent alterations by untargeted proteomics analysis of renal tissues. We observed lysosomal and mitochondrial-related pathways disfunction, higher oxidative stress, as indicated by GSH/GSSH and MDA levels, and higher antioxidant activity in mutant ZF. Moreover, mitochondrial morphological alterations also affecting cristae structure were evident. By immunohistochemistry, we also detected decreased lysosomal Tetraspanin (CD63), Superoxide dismutase 2 (SOD2), and Cadherin 1 (CDH1) protein expression. Thus, this ZF model Gb3-independently mirrors GLA mutation-related changes, and unravels novel FD pathogenic mechanisms, thereby representing a powerful tool for innovative drug screening, and the identification of markers of potential clinical relevance.

2023-10-24 | PXD035409 | Pride

AUTS2 project

Project description:This SuperSeries is composed of the following subset Series: GSE36950: SNP array for CNV calling AUTS2 project [Affymetrix] GSE37141: Oligo array for CNV calling AUTS2 project [Agilent] GSE37142: SNP array for CNV calling AUTS2 project [Illumina] GSE37654: Oligo array for calling CNV's for AUTS2 project [NimbleGen] GSE37656: Oligo array for CNV calling AUTS2 project [Bluegnome] Refer to individual Series

2012-07-11 | E-GEOD-37657 | biostudies-arrayexpress

Targeted Sphingolipid analysis of HeLa silenced for or overexpressing GOLPH3 or LCS

Project description:A group of sequentially-acting enzymes operating at the branchpoint among sphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternae inter-conversion mechanisms. Through these effects, GOLPH3 controls the sub-Golgi localisation, and the lysosomal degradation rate of specific enzymes. Here we evaluated the impact of overexpressing or silencing GOLPH3 or its client enzyme lactosylceramide synthase (LCS) on the sphingolipid composition of HeLa cells by targeted lipid analysis.

2021-01-29 | ST001673 | MetabolomicsWorkbench

Glycogene expression profiles based on microarray data of cervical carcinoma HeLa cells partially silenced in E6 and E7 HPV oncogenes

Project description:Aberrant glycosylation is a characteristic of tumor cells. The expression of certain glycan structures has been associated with poor prognosis. In cervical carcinoma has been reported changes in the gene expression level of some glycogenes that has been associated with lymph invasion. Human papilloma virus (HPV) infection is one of the most important factors to develop cervical cancer. HPV oncoproteins E6 and E7 have been implicated in cervical carcinogenesis. The role of these oncoproteins in glycosylation changes has not been reported. To know the effect of these oncoproteins on glycogene expression we realized a partial silencing of oncogenes E6 and E7 in HeLa cells, we made a microarray expression assay and we identified glycogenes that modified its expression. The analysis showed alteration in some glycosylation pathways, like glycosphingolipid, O-glycan mucin-type, and O-glycan non mucin-type glycosylation. Our results suggest that E6 and E7 oncoproteins could modified glycosylation of structures implicated in proliferation, adhesion, and apoptosis.

2016-12-07 | GSE90930 | GEO

WDR68 is essential for the PRC1-AUTS2 complex activating role and for stem cell differentiation

Project description:Recent studies on Polycomb repressive complexes (PRC) reveal a surprising role in transcriptional activation, yet the underlying mechanism remains poorly understood. We previously identified a type 1 PRC (PRC1) that contains Autism Susceptibility Candidate 2 (AUTS2), which positively regulates transcription of neuronal genes. However, the mechanism by which the PRC1-AUTS2 complex influences neurodevelopment is unclear. Here we demonstrate that WDR68 is not only an integral component of the PRC1-AUTS2 complex, it is required for PRC1-AUTS2-mediated transcription activation. Furthermore, deletion of Wdr68 in mouse embryonic stem cells leads to defects in neuronal differentiation without affecting self-renewal. Through transcriptomic analysis, we found that many genes responsible for neuronal differentiation are down-regulated in Wdr68 deficient neural progenitors. These genes include several that are targeted by the PRC1-AUTS2 complex. In summary, our studies uncovered a previously unknown but essential component of the active PRC1 complex and evidence of its role in regulating the expression of genes that may be important for neuronal differentiation.

2020-07-29 | GSE115576 | GEO

Transcriptomics of induced defense responses to Greenbug aphid feeding in near isogenic wheat lines

Project description:The greenbug aphid, Schizaphis graminum (Rondani) is an important cereal pest periodically threatening wheat yields in the United States and around the world. The wheat breeding program at Texas A&M University has introgressed the greenbug resistance gene Gb3 from synthetic wheat ‘Largo’ into the widely grown cultivars TAM 110 and TAM 112; however, the molecular mechanisms of Gb3-induced defense responses remain unknown. Using Affymetrix GeneChip Wheat Genome Arrays, we investigated the temporal dynamics of Gb3-mediated transcriptional responses upon greenbug feeding on resistant and susceptible bulks (RB and SB respectively) derived from two near-isogenic lines. Following statistical analysis, the MapMan functional classification on 692 differentially expressed transcripts from the interaction group identified 122 transcripts that were putatively associated with biotic stress responses. In RB, Gb3 induced transmembrane receptor kinases and downstream early defense signal transduction pathways. However, non-Gb3 mediated pathways in SB prompted induction of transcripts mediating callose decomposition and transcripts regulating biosynthesis of stress hormones jasmonic acid, ethylene, and abscisic acid. Additionally, the SB showed elevated levels of transcripts mediating redox homeostasis, peroxidases, glutathione S-transferases, and defense-related secondary metabolites. Overall, the results indicated that greenbugs inflicted more damage in the SB compared to RB and absence of Gb3-mediated signaling resulted in cell wall remodeling and strong accumulation of toxic compounds warranting production of antioxidant and defense-related compounds. The study reinforced our knowledge about preferential feeding on S genotypes and plausible antixenosis or tolerance-related defense signaling in Gb3-associated R genotypes and generated several new hypotheses.

2022-01-01 | GSE45995 | GEO

The lipid Gb3 promotes germinal center B cell responses and anti-viral immunity

Project description:Influenza viruses escape immunity due to rapid antigenic evolution, which requires vaccination strategies that allow for broadly protective antibody responses. Here, we demonstrate that the lipid globotriaosylceramide (Gb3) expressed on germinal center (GC) B cells is essential for the production of high-affinity antibodies. Mechanistically, Gb3 binds and disengages CD19 from its chaperone CD81 for subsequent translocation to the B cell receptor (BCR) complex to trigger signaling. Moreover, this lipid regulates MHC-II expression to increase diversity of T follicular helper (Tfh) and GC B cells reactive with subdominant epitopes. In influenza infection, Gb3 promotes broadly reactive antibody responses and cross-protection. Thus, we show that Gb3 determines affinity as well as breadth in B cell immunity and propose this lipid as potential vaccine adjuvant against viral infection.

2023-12-05 | GSE247797 | GEO

Intrahepatic microbes govern liver immunity by programming NKT cells

Project description:The gut microbiome shapes local and systemic immunity. The liver is presumed to be a protected sterile site. As such, a hepatic microbiome has not been examined. Here, we show that the liver hosts a robust microbiome in mice and humans that is distinct from the gut and is enriched in Proteobacteria. It undergoes dynamic alterations with age and is influenced by the environment and host physiology. Fecal microbial transfer experiments revealed that the liver microbiome is populated from the gut in a highly selective manner. Hepatic immunity is dependent on the microbiome, specifically Bacteroidetes species. Targeting Bacteroidetes with oral antibiotics reduced the hepatic immune cell infiltrate by ~90%, prevented APC maturation, and mitigated adaptive immunity. Mechanistically, presentation of Bacteroidetes-derived glycosphingolipids to NKT cells promotes CCL5 signaling, which drives hepatic leukocyte expansion and maturation. Collectively, we reveal a microbial – glycosphingolipid – NKT – CCL5 axis that underlies hepatic immunity.

2022-05-17 | GSE161876 | GEO

An Auts2-Containing RNA-Binding Complex Regulates Transcript Expression in Developing Cerebral Cortex

Project description:Molecular functions of the intellectual disability syndrome gene AUTS2 remain uncertain. Two mechanisms of Auts2 function have been proposed. One study found that Auts2 modifies Polycomb repressive complex 1 (PRC1) to activate transcription of target neurodevelopmental genes by recruiting EP300, a histone acetyltransferase. A second study found that cytoplasmic AUTS2 regulates cytoskeletal assembly through PREX1 to promote neurite outgrowth and migration. To further investigate Auts2 functions, we screened for AUTS2 interactors in cerebral cortex, and profiled changes of transcript expression in the developing cortex of Auts2 conditional mutant mice. AUTS2 immunoprecipitation experiments identified interactions with proteins involved in pre-mRNA processing, and mRNAs, including those encoding EP300 and PREX1, both bound by AUTS2-containing complexes and dysregulated in Auts2 mutant cortex. We propose that AUTS2 interacts with an RNA-binding complex that directly targets transcripts encoding Auts2 effectors. This mechanism provides a unifying model that accounts for previously disparate hypotheses of AUTS2 functions.

2021-05-21 | GSE112792 | GEO

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