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SDHB gene promoter MethylTarget sequencing of normal pregnancy and recurrent spontaneous abortion patients

ABSTRACT: Our study found that low SDHB expression and high succinate levels are important for maintaining embryo implantation in the first trimester; therefore, high SDHB expression and low succinate levels during early pregnancy may increase the risk of RSA. To investigate why villous SDHB expression increases pathologically in RSA but exhibits dynamically low levels during the first trimester followed by high levels under physiological conditions, we detected CpG site methylation levels in the SDHB promoter region of villi from both individuals with RSA and controls.

ORGANISM(S): Homo sapiens

PROVIDER: GSE171877 | GEO | 2021/04/13

REPOSITORIES: GEO

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Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk

Project description:Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

2021-10-06 | MTBLS2148 | MetaboLights

The SDHB Arg230His mutation causing familial paraganglioma alters glycolysis in a new Caenorhabditis elegans model

Project description:The conserved B-subunit of succinate dehydrogenase (SDH) participates in the TCA cycle and mitochondrial electron transport. The Arg230His mutation in SDHB causes heritable pheochromocytoma/paraganglioma (PPGL). In C. elegans, we generated an in vivo PPGL model (SDHB-1 Arg244His; equivalent to human Arg230His) which manifests delayed development, shortened lifespan, attenuated ATP production and reduced mitochondrial number. Although succinate is elevated in both missense and null sdhb-1(gk165) mutants, transcriptomic comparison suggests very different causal mechanisms that are supported by metabolic analysis where only Arg244His (not null) worms elevate lactate/pyruvate levels, pointing to a missense-induced, ‘Warburg’-like aberrant glycolysis. In silico predictions of the SDHA-B dimer structure demonstrate that Arg230His modifies the catalytic cleft despite the latter’s remoteness from the mutation site. We hypothesise that Arg230His SDHB mutation rewires metabolism, reminiscent of metabolic reprogramming in cancer. Our tractable model provides a novel tool to investigate the metastatic propensity of this familial cancer and our approach may illuminate wider SDH pathology.

2020-10-01 | GSE158836 | GEO

A Renal CpG Island Methylator Phenotype (R-CIMP) in Kidney Tumors Associated with Germline Mutations of FH and SDHB

Project description:Germline mutations within the Krebs cycle enzyme genes fumarate hydratase (FH) or succinate dehydrogenase (SDHB, SDHC, SDHD) have been associated with an increased risk of renal cell carcinoma (RCC). These RCCs are characterized by loss of enzyme activity and significantly increased levels of intracellular fumarate or succinate that are predicted to inhibit 2-oxoglutarate-dependent dioxygenases, such as the TET enzymes that regulate DNA methylation. These tumors represent aggressive forms of RCC that can metastasize early and require specific patient management and treatment. Therefore, identifying effective and accurate methods for diagnosing these tumors is very beneficial. This study evaluated and compared the genome-wide methylation profiles of 33 RCCs from patients with RCC susceptibility syndromes, 10 associated normal samples and 13 cell-line models using the Illumina HumanMethylation450 BeadChip assay. Fifteen tumors derived from patients with germline FH (n=9) or SDHB (n=6) mutations demonstrated a distinct pattern of hypermethylation (R-CIMP) with enrichment for hypermethylation within the CpG island regions. A small, selected panel of probes was characterized that could identify R-CIMP and distinguish between FH and SDHB tumors. Cell-line models derived from HLRCC (n=3) or SDHB (n=1) kidney tumors demonstrated similar patterns of hypermethylation to the tumors, yet re-expression of either wild-type FH or SDHB did not alter the hypermethylation pattern. Treatment of the cell line models with 5-aza-2′-deoxycytidine resulted in reduced rates of invasion.

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Cells silenced for SDHB expression and tumor phenotype

Project description:Effect of SDHB silencing using siRNA methodologies in the tumor phenotype We used microarrays to detail the global programme of gene expression when SDHB is silenced. Keywords: siRNA experiment (loss of function)

2008-04-01 | GSE10289 | GEO

Cells silenced for SDHB expression and tumor phenotype

Project description:Effect of SDHB silencing using siRNA methodologies in the tumor phenotype; We used microarrays to detail the global programme of gene expression when SDHB is silenced. Experiment Overall Design: Human hepatocellular carcinoma cell line Hep3B was stably silenced with control or SDHB-specific siRNAs. <br><br>This experiment was re-loaded into ArrayExpress in November 2010 after manual curation.

2008-06-11 | E-GEOD-10289 | biostudies-arrayexpress

Characterizing gene expression changes that accompany succinate dehydrogenase subunit B (SDHB) RNA editing in monocyte-enriched peripheral blood mononuclear cell cultures

Project description:The goal of this study is to identify global changes in gene expression that accompany induction of site-specific RNA editing that targets the SDHB gene in monocyte-enriched peripheral blood mononuclear cell cultures. The results provide important information to understand the function of this programmed SDHB RNA mutation within the context of global gene expression changes that occur in cultured immune cells when the editing is induced. The study also specifically tests whether expression changes occur in SDH subunit genes, cytidine deaminase family of genes and hypoxia-inducible pathways. Overall design includes pairwise comparison of total gene expression profiles from uncultured cold-aggregated PBMCs (day 0), low-editing (culture day 3) and high-editing (culture days 5-8) samples, each from 4 donors. Submitted manuscript reported summary results from comparison of cultured low- and high-editing samples.

2013-04-10 | E-GEOD-45900 | biostudies-arrayexpress

H. sapiens First trimester placental villous explant 0conditioned media; galectin-7/BSA treatment; 2% O2

Project description:Identification of factors in conditioned media of first-trimester placental villous explants. Explants were cultured under hypoxia (2% O2), 5% CO2 in serum-free DMEM/F12 and treated with recombinant galectin-7 (1ug/ml) or vehicle control (BSA) for 72h. Identification of factors in conditioned media of first-trimester placental villous explants. Explants were cultured under superoxia (20% O2), 5% CO2 in serum-free DMEM/F12 and treated with recombinant galectin-7 (1ug/ml) or vehicle control (BSA) for 72h.

2021-04-20 | PXD019331 | Pride

Genome-scale DNA methylation maps of mouse chromaffin cells with or without Sdhb knock-out.

Project description:We report the analysis of DNA methylation in mouse chromaffin cell lines using reduced representation bisulfite sequencing (RRBS). We compared DNA methylation profiles of cell lines with or without a knock-out of Sdhb gene, showing that Sdhb disruption results in a hypermethylator phenotype. Reduced representation bisulfite sequencing of 4 mouse chromaffin cell samples (2 Sdhb wild-type and 2 Sdhb knock-out).

2013-05-06 | E-GEOD-44350 | biostudies-arrayexpress

Genome-scale DNA methylation maps of mouse chromaffin cells with or without Sdhb knock-out.

2013-05-06 | GSE44350 | GEO

Pasteurella multocida strain:SDHB

Project description:Pasteurella multocida strain:SDHB Genome sequencing and assembly

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