|
| Status |
Public on Nov 11, 2021 |
| Title |
scGOF-Seq using ND 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.
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| Overall design |
Adenovirus encoding candidate TF with its corresponding guide-barcode was infected in human nondiabetic islets which are subjected to scRNA-seq.
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| 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 04, 2019 |
| Last update date |
Oct 18, 2022 |
| Contact name |
Hongxu Ding |
| E-mail(s) |
hongxuding@arizona.edu
|
| Organization name |
University of Arizona
|
| Street address |
The University of Arizona
|
| City |
Tucson |
| State/province |
AZ |
| ZIP/Postal code |
85721 |
| Country |
USA |
| |
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| Platforms (2) |
| GPL20301 |
Illumina HiSeq 4000 (Homo sapiens) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
|
| Samples (7)
|
| GSM4060917 |
scGOF-Seq ND donor (ND6) ctrl Dataset 2 |
| GSM4060918 |
scGOF-Seq ND donor (ND6) Dataset 1 |
| GSM4060919 |
scGOF-Seq ND donor (ND6) Dataset 1 (Technical Duplicate) |
| GSM4060920 |
scGOF-Seq ND donor (ND6) Dataset 2 |
|
| Relations |
| BioProject |
PRJNA563923 |
| SRA |
SRP220373 |
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