التفاصيل البيبلوغرافية
| العنوان: |
Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines |
| المؤلفون: |
Benaglio, Paola, Zhu, Han, Okino, Mei Lin, Yan, Jian, Elgamal, Ruth, Nariai, Naoki, Beebe, Elisha, Korgaonkar, Katha, Qiu, Yunjiang, Donovan, Margaret K.R., Chiou, Joshua, Wang, Gaowei, Newsome, Jacklyn, Kaur, Jaspreet, Miller, Michael, Preissl, Sebastian, Corban, Sierra, Aylward, Anthony, Taipale, Jussi, Ren, Bing, Frazer, Kelly A., Sander, Maike, Gaulton, Kyle J. |
| المساهمون: |
Department of Pathology, Biosciences, Doctoral Programme in Integrative Life Science, Jussi Taipale / Principal Investigator |
| بيانات النشر: |
Elsevier Inc. |
| سنة النشر: |
2023 |
| المجموعة: |
Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto |
| مصطلحات موضوعية: |
3D chromatin interactions, accessible chromatin, beta cell, CRISPR screen, functional genomics, gene expression, high-throughput reporter assay, human genetics, proinflammatory cytokines, type 1 diabetes, General medicine, internal medicine and other clinical medicine, Biomedicine |
| الوصف: |
We combined functional genomics and human genetics to investigate processes that affect type 1 diabetes (T1D) risk by mediating beta cell survival in response to proinflammatory cytokines. We mapped 38,931 cytokine-responsive candidate cis-regulatory elements (cCREs) in beta cells using ATAC-seq and snATAC-seq and linked them to target genes using co-accessibility and HiChIP. Using a genome-wide CRISPR screen in EndoC-βH1 cells, we identified 867 genes affecting cytokine-induced survival, and genes promoting survival and up-regulated in cytokines were enriched at T1D risk loci. Using SNP-SELEX, we identified 2,229 variants in cytokine-responsive cCREs altering transcription factor (TF) binding, and variants altering binding of TFs regulating stress, inflammation, and apoptosis were enriched for T1D risk. At the 16p13 locus, a fine-mapped T1D variant altering TF binding in a cytokine-induced cCRE interacted with SOCS1, which promoted survival in cytokine exposure. Our findings reveal processes and genes acting in beta cells during inflammation that modulate T1D risk. ; Peer reviewed |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
English |
| العلاقة: |
The work performed in this study was supported by NIH grants DK122607 and DK120429 to K.J.G. and M.S.; DK112155 to M.S., K.F., K.J.G., and B.R.; and DK105541 to M.S., K.F., and B.R. The work performed in this study was supported by NIH grants DK122607 and DK120429 to K.J.G. and M.S.; DK112155 to M.S. K.F. K.J.G. and B.R.; and DK105541 to M.S. K.F. and B.R. K.J.G. and M.S. conceived of and supervised the study. K.J.G. P.B. H.Z. M.O. and M.S. wrote the manuscript. J.T. and B.R. supervised the design and generation of SNP-SELEX data. K.F. supervised the design of SNP-SELEX and analyses of genomic data. S.P. supervised generation of single-cell data. P.B. performed statistical data analysis of genomic, CRISPR-KO screen, and genetic data; H.Z. performed the CRISPR-KO screen and interpreted the results; M.O. and M.M. performed genomic assays. J.Y. performed the SNP-SELEX assay. P.B. M.O. R.E. E.B. K.K. A.A. J.C. G.W. and J.N. performed bulk and single-cell data analysis. M.O. R.E. J.K. and S.C. performed functional validation experiments. P.B. N.N. Y.Q. A.A. and M.K.D. performed design and analysis of SNP-SELEX data. All authors contributed to and approved of the final version of the manuscript. K.J.G. is a consultant of Genentech and holds stock in Neurocrine Biosciences. B.R. is a consultant of Arima Genomics and a co-founder of Epigenome Technologies. P.B. is an employee of Shoreline Bioscience. N.N. is an employee of Guardant Health. E.B. is an employee and shareholder of Aetion. K.K. is an employee of Cartography Bio. Y.Q. is an employee of Sana Biotechnology. M.D. is an employee and shareholder of Seer. J.C. is an employee and shareholder of Pfizer.; Benaglio , P , Zhu , H , Okino , M L , Yan , J , Elgamal , R , Nariai , N , Beebe , E , Korgaonkar , K , Qiu , Y , Donovan , M K R , Chiou , J , Wang , G , Newsome , J , Kaur , J , Miller , M , Preissl , S , Corban , S , Aylward , A , Taipale , J , Ren , B , Frazer , K A , Sander , M & Gaulton , K J 2022 , ' Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines ' , Cell genomics , vol. 2 , no. 12 , 100214 . https://doi.org/10.1016/j.xgen.2022.100214Test; http://hdl.handle.net/10138/354977Test; c6a62712-0c8b-4078-9442-a6813e9052b5; 85143868567 |
| الإتاحة: |
http://hdl.handle.net/10138/354977Test |
| حقوق: |
cc_by_nc_nd ; info:eu-repo/semantics/openAccess ; openAccess |
| رقم الانضمام: |
edsbas.750AFFCF |
| قاعدة البيانات: |
BASE |
