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Series GSE137766 Query DataSets for GSE137766
Status Public on Nov 11, 2021
Title Perturb-Seq using T2D islets
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Type 2 diabetes is associated with defective insulin secretion and reduced β-cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of b-cell failure is a key translational question. Here, we reverse-engineered and interrogated pancreatic islet-specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic-inflexibility and endocrine-progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca++ flux analyses of top candidate MR in islet cells validated transcription factor BACH2 and associated epigenetic effectors as a key driver of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a non-diabetic phenotype. BACH2-immunoreactive islet cells increased ~4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing b-cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.
Overall design Adenovirus encoding CAS9_gRNAs targetting candidate TF with its corresponding DNA guide-barcode was infected in human T2D islets which are subjected to scRNA-seq.
Contributor(s) Son J, Ding H, Califano A, Accili D
Citation(s) 34907913
NIH grant(s)
Grant ID Grant title Affiliation Name
R01 DK064819 Mechanisms of Beta Cell Failure Trustees of Columbia University in the City of New York DOMENICO ACCILI
R35 CA197745 Elucidating the dependencies of tumor initiating and drug-resistant niches in human malignancies by genome- wide molecualr profiling of single cells Trustees of Columbia University in the City of New York ANDREA CALIFANO
P30 DK063608 Columbia Diabetes Research Center Trustees of Columbia University in the City of New York DOMENICO ACCILI
F32 DK117574 Analysis of beta cell dedifferentiation using scRNA-seq of human T2D Trustees of Columbia University in the City of New York Jinsook Son
Submission date Sep 19, 2019
Last update date Oct 07, 2022
Contact name Hongxu Ding
Organization name University of Arizona
Street address The University of Arizona
City Tucson
State/province AZ
ZIP/Postal code 85721
Country USA
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (4)
GSM4087037 Perturb-Seq T2D donor (T2D7) ctrl Dataset 1
GSM4087038 Perturb-Seq T2D donor (T2D7) ctrl Dataset 2
GSM4087039 Perturb-Seq T2D donor (T2D7) Dataset 1
BioProject PRJNA568200
SRA SRP222610

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Supplementary file Size Download File type/resource
GSE137766_RAW.tar 76.8 Mb (http)(custom) TAR (of CSV)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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