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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (MCC)

ABSTRACT: Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (MCC)

PROVIDER: PRJNA733668 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR14685310_1.fastq.gz	Fastqsanger.gz
	SRR14685310_2.fastq.gz	Fastqsanger.gz
	SRR14685311_1.fastq.gz	Fastqsanger.gz
	SRR14685311_2.fastq.gz	Fastqsanger.gz
	SRR14685312_1.fastq.gz	Fastqsanger.gz

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Project description:Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (ChIP-seq)

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (ATAC-seq)

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (MCC)

Project description:To identify regulatory interactions in erythroid, fibroblast and endothelial cells Micro Caputre-C was carried outfrom the promoters of active genes as well as the rs17713054 containing enhancer.

2021-08-31 | GSE175790 | GEO

Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus

Project description:To identify a causative variant and effector gene responsible for a 2-fold increased risk of severe COVID-19, a multi-omics platform was deployed. A combination of ATAC-seq, ChIP-seq, Micro Capture-C and NuTi Capture-C were used to characterize a range of cell types, including epithelial, fibroblast, endothelial, immune and erythroid cells.

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Microarray analysis of Merkel cell carcinoma (MCC) tumors, small cell lung cancer (SCLC) tumors, and MCC cell lines

Project description:When using cell lines to study cancer, phenotypic similarity to the original tumor is paramount. Yet, little has been done to characterize how closely Merkel cell carcinoma (MCC) cell lines model native tumors. To determine their similarity to MCC tumor samples, we characterized MCC cell lines via gene expression microarrays. Using whole transcriptome gene expression signatures and a computational bioinformatic approach, we identified significant differences between variant cell lines (UISO, MCC13, and MCC26) and fresh frozen MCC tumors. Conversely, the classic WaGa and Mkl-1 cell lines more closely represented the global transcriptome of MCC tumors. When compared to publicly available cancer lines, WaGa and Mkl-1 cells were similar to other neuroendocrine tumors, but the variant cell lines were not. WaGa and Mkl-1 cells grown as xenografts in mice had histological and immunophenotypical features consistent with MCC, while UISO xenograft tumors were atypical for MCC. Spectral karyotyping and short tandem repeat analysis of the UISO cells matched the original cell line's description, ruling out contamination. Our results validate the use of transcriptome analysis to assess the cancer cell line representativeness and indicate that UISO, MCC13, and MCC26 cell lines are not representative of MCC tumors, whereas WaGa and Mkl-1 more closely model MCC. RNA was extracted from MCC cell lines and MCC and SCLC tumor samples and hybridized to Affymetrix microarrays for transcriptome profiling.

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MCC regulator of WNT signaling pathway (MCC) is a podocyte essential gene

Project description:Podocytes are an integral part of the glomerular infiltration barrier. At present, many genes are known essential for podocyte survival and structural and functional homeostasis; however, there are more such genes to be uncovered. By single-cell RNA-seq of mouse podocytes, we detected the expression of gene encoding MCC regulator of WNT signaling pathway (MCC) in majority of the single podocytes and speculated that MCC may be essential for podocytes. We confirmed MCC expression in mouse podocytes and further showed its expression in human podocytes. To experimentally prove the essentiality of MCC for podocytes, we knocked down MCC in cultured podocytes, resulting in marked morphological change of cell shape, cytoskeletal stress fiber disruption, increased apoptosis, and downregulation of podocyte essential genes, CD2AP and WT1, demonstrating that MCC is essential for podocytes. To investigate the mechanism underlying the role of MCC in podocytes, we performed RNA-seq analysis of the podocytes in culture 24 hours after transfection of siRNA against MCC, followed by bioinformatics analysis of the genes with altered expression, and found some mechanistic clues. Lastly, we found that MCC is downregulated in podocytes treated with puromycin aminonucleosides and in glomeruli of diabetic mice and FSGS patients, implicating MCC in the development of podocytopathy and proteinuria. In conclusion, MCC is essential for podocytes and its deficiency may be involved in podocytopathy.

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (ATAC-seq)

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus (ChIP-seq)

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Identification of LZTFL1 as a candidate effector gene at a COVID-19 risk locus.

Project description:The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) disease (COVID-19) pandemic has caused millions of deaths worldwide. Genome-wide association studies identified the 3p21.31 region as conferring a twofold increased risk of respiratory failure. Here, using a combined multiomics and machine learning approach, we identify the gain-of-function risk A allele of an SNP, rs17713054G>A, as a probable causative variant. We show with chromosome conformation capture and gene-expression analysis that the rs17713054-affected enhancer upregulates the interacting gene, leucine zipper transcription factor like 1 (LZTFL1). Selective spatial transcriptomic analysis of lung biopsies from patients with COVID-19 shows the presence of signals associated with epithelial-mesenchymal transition (EMT), a viral response pathway that is regulated by LZTFL1. We conclude that pulmonary epithelial cells undergoing EMT, rather than immune cells, are likely responsible for the 3p21.31-associated risk. Since the 3p21.31 effect is conferred by a gain-of-function, LZTFL1 may represent a therapeutic target.

| S-EPMC7611960 | biostudies-literature

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