Ontology highlight
ABSTRACT:
PROVIDER: PRJNA726976 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:A genome-wide CRISPR screen identifies regulators of beta cell function involved in type 2 diabetes risk
| PRJEB44712 | ENA
Project description:Proinsulin is the precursor of insulin in pancreatic beta cells. Altered proinsulin and proinsulin to insulin ratio mark beta cell dysfunction, predictuing disease progression into type 1 and type 2 diabetes. Of essential role for beta cell function, knowledge about proinsulin production and its role in disease are currently very limited. Using genome wide CRISPR screen, we identified 84 proinsulin regulators including classical protein convertases Pcsk1 and Cpe, and novel factors like Pdia6. Among the list 29 proinsulin regulators were trajectory genes involved in disease progression in obesity and type 2 diabetes in humans. In vivo mouse genetics study revealed unique genetic architecture and quantitative trait loci (QTLs) modulating plasma proinsulin levels. Integrative analyzing and mapping of the QTL signals directly pinpointed to proinsulin regulators identified from the CRISPR screen, which in return greatly improved resolution of the mouse genetic study. 4 out of 5 overlapped genes can be individually validated. Knocking down the leading hits Pdia6 leads to decreased proinsulin content and remarkable loss of proinsulin granules in beta cells. Consequently, proinsulin secretion was greatly decreased. Mechanistically, protein translation rate was greatly impaired after knocking down Pdia6. Our study demonstrated the power of combining in vitro functional genomics with in vivo mouse genetics study to identify proinsulin regulatory network in pancreatic beta cells.
2023-11-15 | GSE245845 | GEO
Project description:Proinsulin is the precursor of insulin in pancreatic beta cells. Altered proinsulin and proinsulin to insulin ratio mark beta cell dysfunction, predictuing disease progression into type 1 and type 2 diabetes. Of essential role for beta cell function, knowledge about proinsulin production and its role in disease are currently very limited. Using genome wide CRISPR screen, we identified 84 proinsulin regulators including classical protein convertases Pcsk1 and Cpe, and novel factors like Pdia6. Among the list 29 proinsulin regulators were trajectory genes involved in disease progression in obesity and type 2 diabetes in humans. In vivo mouse genetics study revealed unique genetic architecture and quantitative trait loci (QTLs) modulating plasma proinsulin levels. Integrative analyzing and mapping of the QTL signals directly pinpointed to proinsulin regulators identified from the CRISPR screen, which in return greatly improved resolution of the mouse genetic study. 4 out of 5 overlapped genes can be individually validated. Knocking down the leading hits Pdia6 leads to decreased proinsulin content and remarkable loss of proinsulin granules in beta cells. Consequently, proinsulin secretion was greatly decreased. Mechanistically, protein translation rate was greatly impaired after knocking down Pdia6. Our study demonstrated the power of combining in vitro functional genomics with in vivo mouse genetics study to identify proinsulin regulatory network in pancreatic beta cells.
2023-11-15 | GSE245844 | GEO
Project description:Replenishment of pancreatic beta cells is a key to the cure for diabetes. Beta cell regeneration is achieved predominantly by self-replication, especially in rodents, but it was also shown that pancreatic duct cells can transdifferentiate into beta cells. How pancreatic duct cells are transdifferentiated and whether we can manipulate transdifferentiation to replenish beta cell mass is not well understood. Using a genome-wide Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) screen, we found that loss-of-function of Aldehyde dehydrogenase family 3 member B2 (ALDH3B2) was sufficient to transdifferentiate human pancreatic duct cells into functional beta-like cells. The transdifferentiated cells had substantially increased expression of beta cell marker genes, secreted insulin in response to glucose, and lowered blood glucose to near normal when transplanted into streptozotocin (STZ)-induced diabetic mice for 6 weeks. Our study identifies a gene that could potentially be targeted in human pancreatic duct cells to replenish beta cell mass for diabetes therapy.
2026-06-27 | GSE336774 | GEO
Project description:Beta cells intrinsically contribute to the pathogenesis of type 1 diabetes (T1D), but the genes and molecular processes that mediate beta cell survival in T1D remain largely unknown. We combined high throughput functional genomics and human genetics to identify T1D risk loci regulating genes affecting beta cell survival in response to the proinflammatory cytokines IL-1b, IFNg, and TNFa. We mapped cytokine-responsive candidate cis-regulatory elements (cCREs) active in beta cells using ATAC-seq and single nuclear ATAC-seq (snATAC-seq), and linked cytokine-responsive beta cell cCREs to putative target genes using single cell co-accessibility and HiChIP. We performed a genome-wide pooled CRISPR loss-of-function screen in EndoC-βH1 cells, which identified hundreds of genes affecting cytokine-induced beta cell loss. We identified thousands of variants in cytokine-responsive beta cell cCREs altering transcription factor (TF) binding using high-throughput SNP-SELEX. Together our findings reveal processes and genes acting in beta cells during cytokine exposure that intrinsically modulate risk of T1D.
2022-10-31 | GSE205853 | GEO
Project description:To search for factors regulating neuronal differentiation, we performed a genome-wide loss-of-function CRISPR/Cas9 screen in haploid human ESCs. The regulators were identified by the quantification of depletion of their mutant clones within a pooled loss-of-function library upon neuronal differentiation.
2024-01-12 | E-MTAB-11944 | biostudies-arrayexpress
Project description:Genome-wide CRISPR screen to identify CD58 regulators
| PRJNA934388 | ENA
Project description:To search for host factors regulating Zika virus infection, we performed a genome-wide loss-of-function CRISPR/Cas9 screen in haploid human ESCs. The regulators were identified by the quantification of enrichment of their mutant clones within a pooled loss-of-function library upon Zika virus infection.
2023-05-31 | E-MTAB-11945 | biostudies-arrayexpress
Project description:To search for host factors regulating SARS-COV-2 infection, we performed a genome-wide loss-of-function CRISPR/Cas9 screen in haploid human ESCs. The regulators were identified by the quantification of enrichment of their mutant clones within a pooled loss-of-function library upon SARS-COV-2 infection.
2023-08-09 | E-MTAB-12505 | biostudies-arrayexpress
Project description:Genome-wide CRISPR/Cas9-based screen to identify positive regulators of p53 function
2022-12-19 | GSE189132 | GEO