Dataset Information

Functional characterization of the novel SDR42E1 reveals its role in vitamin D biosynthesis

ABSTRACT: Vitamin D deficiency poses a major global health challenge, shaped by environmental and genetic determinants. In this genetic context, the recently discovered rs11542462 nonsense variant in the short-chain dehydrogenase/reductase 42E1 (SDR42E1) gene emerges as a critical regulator, though its biological implications remain largely unexplored. Our comprehensive bioinformatic assessments revealed pronounced expression of SDR42E1 in skin keratinocytes and the analogous HaCat human keratinocyte cell lines, prompting us to select the latter as an experimental model. Employing CRISPR/Cas9 technology and an integrated multi-omics approach, combining transcriptomics and proteomics, we explored SDR42E1's functions, focusing on its localization, role in lipid and steroid biosynthesis, and the consequent effects on vitamin D biosynthesis. We highlighted the significant cytoplasmic presence of the SDR42E1 protein, essential for lipid and steroid production. Our whole transcriptomics analysis of the SDR42E1 depleted model showed a notable disruption in the steroid biosynthesis pathway by 1.6-fold (P = 0.03). This disruption was accompanied by considerable alterations in genes involved in vitamin D synthesis, a finding supported by our proteomics data. Notably, SERPINB2 (P = 2.17E−103), EBP (P = 2.46E−13), and DHCR7 (P = 8.03E−09) showed significant elevations by ~2-3 fold, while ALPP (P < 2.2E−308), SLC7A5 (P = 1.96E−215), and CYP26A1 (P = 1.06E−08) decreased by ~1.5-3 fold. These alterations led to an accumulation of 7-dehydrocholesterol, preventing its conversion to vitamin D3, as evidenced by our drug enrichment analysis (P = 4.39E−06). This investigation unveils SDR42E1's pivotal role in vitamin D homeostasis and its broader impact on metabolic pathways. Our findings provide a foundation for future research and highlight the potential of precision medicine in addressing vitamin D deficiency, offering significant insights into the genetic regulation of vitamin D biosynthesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262704 | GEO | 2024/08/22

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Steroidogenic acute regulatory protein (Star) facilitates cholesterol transfer into the inner mitochondrial membrane in the acute and regulated production of steroid hormones. Mice lacking Star (Star-/-) share the phenotypes with patients with congenital lipoid adrenal hyperplasia such as compromised production of steroid hormones and florid accumulation of cholesterol esters in adrenal glands and gonads. To define specific patterns of molecular changes with disruption of Star, we performed a transcriptome analysis of steroidogenic cells in adrenal glands. We harvested adrenal glands at E17.5 or 18.5 from seven wild-type (Star+/+) mice or four Star-/- mice having the transgene targeting enhanced green fluorescent protein (eGFP) under the control of regulatory sequences of mouse Star gene. Steroidogenic cells were selectively isolated by fluorescent-activated cell sorting. The gene expression profile of the fluorescence-positive cells was obtained with Agilent Whole Mouse Genome Microarray and was confirmed by quantitative real-time PCR. We identified 961 and 622 genes that were significantly up-regulated and down-regulated, respectively, in Star-/- mice compared with Star+/+ mice (fold difference ≥2, p value of Student t test <0.05, and Benjamini-Hochberg false discovery rate of multiple comparison test <0.2). In Star-/- mice, expression levels of genes involved in cholesterol mobilization and efflux or immune response as antigen presenting cells were significantly increased, and transition from fetal to adult adrenocortical cells were significantly decreased, whereas those of genes related to steroid hormone biosynthesis or cholesterol biosynthesis and influx were not significantly changed. The trancriptome analysis revealed hitherto undescribed characteristic changes in adrenocortical cells and expanded our understanding of the pathophysiology of the steroidogenic cells with disruption of Star. Gene expression profiles of isolated adrenal steroidogenic cells were compared between seven wild-type mice and four knockout mice lacking steroidogenic acute regulatory protein at E17.5-18.5.

Project description:The modes of triazole reproductive toxicity have been characterized by an observed increased in serum testosterone and reduced insemination and fertility indices. The key events involved in the disruption in testosterone homeostasis and reduced fertility remain unclear. Gene expression analysis was conducted on liver and testis from Wistar Han IGS rats fed myclobutanil (M: 500, 2000 ppm), propiconazole (P: 500, 2500 ppm), or triadimefon (T: 500, 1800 ppm) from gestation day six to postnatal day 92. Pathway-based analysis highlighted key biological processes affected by all three triazoles in the liver including fatty acid catabolism, steroid metabolism, and xenobiotic metabolism. Triadimefon induced a distinctive expression profile of genes involved in liver sterol biosynthesis. There were no common pathways modulated by all three triazoles in the testis. Within the pathways identified in the liver, specific genes involved in phase I-III metabolism (Aldh1a1, Cyp1a1, Cyp2b2, Cyp3a1, Slco1a4, Udpgtr2), fatty acid metabolism (Cyp4a10, Pc, Ppap2b), and steroid metabolism (Srd5a1, Ugt1a1, Ugt2a1) were affected by all three triazoles. These modulated genes are part of a network of lipid and testosterone homeostasis pathways regulated by the constitutive androstane (CAR) and pregnane X (PXR) receptors. Gene expression profiles from this study indicate triazoles activate CAR and PXR; increase fatty acid catabolism, sterol biosynthesis, and steroid metabolism in the liver; constituting a plausible series of key events contributing to the observed disruption in testosterone homeostasis. Experiment Overall Design: A total of 34 testis samples were analyzed. Seven biological replicates for control, 4 biological replicates for mid dose myclobutanil, 5 biological replicates for high dose myclobutanil, 4 biological replicates for mid dose propiconazole, 5 biological replicates for high dose propiconazole, 4 biological replicates for mid dose triadimefon, and 5 biological replicates for high dose triadimefon.

Project description:The modes of triazole reproductive toxicity have been characterized by an observed increased in serum testosterone and reduced insemination and fertility indices. The key events involved in the disruption in testosterone homeostasis and reduced fertility remain unclear. Gene expression analysis was conducted on liver and testis from Wistar Han IGS rats fed myclobutanil (M: 500, 2000 ppm), propiconazole (P: 500, 2500 ppm), or triadimefon (T: 500, 1800 ppm) from gestation day six to postnatal day 92. Pathway-based analysis highlighted key biological processes affected by all three triazoles in the liver including fatty acid catabolism, steroid metabolism, and xenobiotic metabolism. Triadimefon induced a distinctive expression profile of genes involved in liver sterol biosynthesis. There were no common pathways modulated by all three triazoles in the testis. Within the pathways identified in the liver, specific genes involved in phase I-III metabolism (Aldh1a1, Cyp1a1, Cyp2b2, Cyp3a1, Slco1a4, Udpgtr2), fatty acid metabolism (Cyp4a10, Pc, Ppap2b), and steroid metabolism (Srd5a1, Ugt1a1, Ugt2a1) were affected by all three triazoles. These modulated genes are part of a network of lipid and testosterone homeostasis pathways regulated by the constitutive androstane (CAR) and pregnane X (PXR) receptors. Gene expression profiles from this study indicate triazoles activate CAR and PXR; increase fatty acid catabolism, sterol biosynthesis, and steroid metabolism in the liver; constituting a plausible series of key events contributing to the observed disruption in testosterone homeostasis. Experiment Overall Design: A total of 35 liver samples were analyzed. Seven biological replicates for the controls, 5 biological replicates for mid dose myclobutanil and 5 biological replicates for high dose mylcobutanil. There are 5 biological replicates for mid dose propiconazole, 4 biological replicates for high dose propiconazole, 5 biological replicates for mid dose triadimefon, and 4 biological replicates for triadimefon.

Dataset Information

Functional characterization of the novel SDR42E1 reveals its role in vitamin D biosynthesis

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure