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

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

PROVIDER: PRJNA1093038 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28490629_1.fastq.gz	Fastqsanger.gz
	SRR28490629_2.fastq.gz	Fastqsanger.gz
	SRR28490630_1.fastq.gz	Fastqsanger.gz
	SRR28490630_2.fastq.gz	Fastqsanger.gz
	SRR28490631_1.fastq.gz	Fastqsanger.gz

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Project description: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.

Project description:Heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2 plays a pivotal role in vitamin D receptor (VDR) signaling by acting as a vitamin D response element (VDRE)-binding protein (VDRE-BP). Transcriptional regulation by active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) involves occupancy of VDRE by VDRE-BP or 1,25(OH)2D3 bound-VDR. This relationship is disrupted by over-expression of VDRE-BP and can cause a form of human hereditary vitamin D-resistant rickets (HVDRR). DNA array analyses using B-cells from an HVDRR patient and matched control defined a sub-cluster of genes where 1,25(OH)2D3-regulated transcription was abrogated by over-expression of VDRE-BP. Amongst these, the DNA-damage-inducible transcript 4 (DDIT4), an inhibitor of mammalian target of rapamycin (mTOR) signaling, was also induced by 1,25(OH)2D3 in human osteoblasts. Chromatin immunoprecipitation using 1,25(OH)2D3-treated osteoblasts confirmed that liganded VDR and VDRE-BP compete for binding to the proximal promoter of the DDIT4 gene in a similar fashion to other known 1,25(OH)2D3-target genes. Treatment of osteoblasts with 1,25(OH)2D3 induced DDIT4 expression and suppressed phosphorylated S6K1T389 protein (a downstream target of mTOR). The functional importance of this for 1,25(OH)2D3 responses in osteoblasts was underlined by the fact that siRNA knockdown of DDIT4 expression suppressed antiproliferative and cell growth responses to 1,25(OH)2D3. These data confirm that VDRE-BP is required for normal 1,25(OH)2D3-mediated transcription and cell function in osteoblasts. Conversely over-expression of VDRE-BP exerts a dominant-negative effect on transcription of 1,25(OH)2D3-target genes. Characterization of VDRE-BP action in 1,25(OH)2D3-treated osteoblasts highlights an entirely novel role for vitamin D as a regulator of mTOR – a known ‘master regulator’ of cell function. We performed gene expression microarray analysis in HVDRR EBV-transformed B-cells and control cells in the presence or absence of vitamin D.

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

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