{"database":"EGA","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"study_type":["Transcriptome Analysis"],"full_dataset_link":["https://ega-archive.org/studies/EGAS00001006273"],"host":["EGA"],"description":["EGA study EGAS00001006273"],"dataset_title":["Islet RFX6 Study Manuscript Data"],"repository":["EGA"],"category":["restricted"],"name_synonyms":["T2DM - Type 2 Diabetes mellitus, Adult-Onset Diabetes Mellitus, Diabetes Type 2, type 2, d230, human being, Noninsulin Dependent, dTAFII250, Type 2 Diabetes Mellitus, DIABETES MELLITUS TYPE 02, EfW1, diabetes mellitus type 2, Maturity-onset diabetes, Human, dmTAF[[II]]230, Homo sapiens, dmTAF1, Taf230, Non-Insulin-Dependent, Non-Insulin Dependent Diabetes Mellitus, Maturity Onset Diabetes, non-insulin-dependent diabetes mellitus, DmF2, Fs(3)Hor, Slow Onset, Man, Maturity-Onset Diabetes, TAF250, lod, T2DM, Taf200, DmelCG2684, dTAF[[II]]250, Man (Taxonomy), TFIID TAF250, cel, cell, Non-Insulin-Dependent Diabetes Mellitus, dysfunction, Taf1p, Maturity Onset Diabetes Mellitus, NTef2, adult-onset, Stable Diabetes Mellitus., Ketosis-Resistant Diabetes Mellitus, NIDDM, dTAF250, Noninsulin-Dependent, Diabetes mellitus, Maturity-onset diabetes mellitus, Noninsulin Dependent Diabetes Mellitus, Stable, MODY (Maturity-onset diabetes of the young), Diabetes Mellitus, Ketosis-Resistant, TAF, Non Insulin Dependent, Diabetes, Adult Onset, Type 2 diabetes, dTAF[[II]]230, TAF[[II]]250, Adult-onset diabetes, Type 2 diabetes mellitus, Adult-onset diabetes mellitus, Modern, MTFS, TAF200, MODY, l(3)84Ab, BG:DS00004.13, TAFII-250, TAF250/230, 4930572O07Rik, dJ955L16.1, Cell, RFXDC1, Noninsulin-dependent diabetes mellitus, Fs(3)Sz11, dTAF230, Adult-Onset, TAFII250, T2D, MTCHRS, Adult-Onset Diabetes, Rfxdc1, p230, Slow-Onset Diabetes Mellitus, Maturity-Onset, TAF[[II]]250/230, TFIID, Type 2 Diabetes Mellitus Non-Insulin Dependent, Ketosis Resistant, Maturity-Onset Diabetes Mellitus, Taf[[II]]250, Type 2 Diabetes, TAF[[II]]230, Type II Diabetes, TAF[II]250, pathophysiology, Type 2, CG17603, Lds, TAF[[II]], human, early, Noninsulin-Dependent Diabetes Mellitus, type II, DmelCG17603, non-insulin-dependent, Non-Insulin Dependent Diabetes, Taf250, SR3-5, Horka, Modern Man, CG2684, Fs(3)Horka, Type II, Slow-Onset, Maturity Onset, TAF230, TAF1"],"description_synonyms":["Soluble, Adult-Onset Diabetes Mellitus, type 2, Written Materials, T-cell leukemia, Materials, acetylglucosaminyltransferase-like protein, AGL4, Type 2 Diabetes Mellitus, insuline humaine, Profiles, l(2)E41, prevention, Case Fatality Rates, dmTAF[[II]]230, Death Rates, Associations, island of pancreas, Non-Insulin Dependent Diabetes Mellitus, Excess Mortalities, Fs(3)Hor, myd, molecules, Endocrine, TFIID TAF250, CG10619, like-acetylglucosaminyltransferase, Genomes, cel, plant peltate hair, Tissue, F10N7_150, Mbp-1, Molekuel, NTef2, Signatures, Ketosis-Resistant Diabetes Mellitus, NIDDM, Noninsulin-Dependent, Isl, Secretion, Diabetes mellitus, Expression Signature, Role Concepts, Homo sapiens disease, Tissue Donor, stage, zinc ion regulated proximal promoter sequence-specific DNA binding, Age-Specific Death Rate, Materials Translation, TRANSCRIPTION FACTOR, RNA polymerase II distal enhancer sequence-specific binding, insulinum humanum, RNA polymerase II core promoter proximal region sequence-specific binding, isl, Nervous system-specific RNA-binding protein Hel-N1, dTAF[[II]]230, Regular, preventive therapy, Transplant Donor, Adult-onset diabetes mellitus, Transplant, MTFS, Crude Death, TAF200, Semen Donors, islets of Langerhans, Fs(3)Sz11, Regular Insulin, insulin (recombinant), el-1, DmIKKgamma, Role Concept, Adult-Onset Diabetes, Islet, dIKK, mKIAA0609, Expression Signatures, Role, atomo, simple tissue, Donors, HuB, Ketosis Resistant, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, Pancreatic, atome, Soluble Insulin, Expression Profile, ELAV-like neuronal protein 1, Maturity-Onset Diabetes Mellitus, Translations, fg, HELN1, death rate, Written Materials Translations, atoms, IKK-gamma, Type II Diabetes, insulina humana, F14P3_4, Hub, HUB, INSDC_feature:gene, whole genome, elrB, surveillance, Pancreas, Transcription factor, human, Semen Donor, MDC1D, Mortality Rate, non-insulin-dependent, enr, Taf250, Material, Festa, Cells, CG2684, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, hub, Mortality Determinant, Slow-Onset, Organ Donors, metal ion regulated sequence-specific DNA binding, TAF230, T2DM - Type 2 Diabetes mellitus, developmental stage, peltate hair, islet of Langerhans, Excess, Crude Mortality Rate, SEPALLATA 2, Islets, Transcription Factor, LARGE1, Maturity-onset diabetes, dIKK-gamma, Nervous system-specific RNA-binding protein Mel-N1, Age-Specific Death, Pancreatic Islet, Human, pancreatic islet, Rate, Determinant, zinc ion regulated core promoter proximal region sequence-specific DNA binding, Insulin, DmIKK-gamma, disease or disorder, Case Fatality, Medical, heln1, Man, U19, Chain, Differential Mortality, Endocrine Pancreas, Transcription, BM040, Excess Mortality, dTAF[[II]]250, Clinical, occurrence, cell, islet, MDDGB6, Profile, dysfunction, prevalence, adult-onset, DmelCG10619, Transplant Donors, dTAF250, Insulin recombinant, RNA polymerase II proximal promoter sequence-specific DNA binding, Diabetes Mellitus, copper ion regulated proximal promoter sequence-specific DNA binding, Crude Death Rates, Ovum Donor, atom, Organ, Mortality Decline, disorders, MODY, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, BG:DS00004.13, function, Factor, 4930572O07Rik, Cell, dJ955L16.1, dTAF230, Concept, Case Fatality Rate, IKKgamma, T2D, Rfxdc1, Gene Expression Signatures, Insulin A Chain, Slow-Onset Diabetes Mellitus, Maturity-Onset, TAF[[II]]250/230, RNA polymerase II transcription factor activity, condition, Sodium, Donor, Novolin, scales, Islands of Langerhans, Death, outbreaks, Taf[[II]]250, Death Rate, underdeveloped, Dmikkgamma, prophylaxis, Nesidioblast, nucleus of neuraxis, Understanding, metal ion regulated core promoter proximal region sequence-specific binding, Lds, CG16910, F10N7.150, Hu-antigen B, Differential, Xel-1, like-glycosyltransferase, control, Gene Expression Profiles, Tup, Decline, epidemics, Stable Diabetes Mellitus, Differential Mortalities, Diabetes Type 2, Insulin B Chain, scale tissue, Mbp1, Gene Expression Profile, neutral molecular compounds, diabetes mellitus type 2, element, Readability, diseases, Roles, human insulin, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, horsetail nucleus, Concepts, Maturity Onset Diabetes, Written, diseases and disorders, l(2)37Aa, AW048865, Langerhans Islands, hel-n1, Slow Onset, prevention and control, molecule, Chromatins, IKKg, KEY, Key, molecula, insulin, DmelCG2684, human disease, Man (Taxonomy), reference sample, Crude Mortality Rates, hypoplasia, island of Langerhans, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, preventive measures, insulin human, pancreatic insula, MODY (Maturity-onset diabetes of the young), CFR Case Fatality Rate, chromosome scaffold, AGAMOUS-like 4, Transcriptomes, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, Non Insulin Dependent, nuclear chromatin, wide/broad, gyltl1b-b, frequency, Modern, Written Materials Translation, Expression Profiles, TAFII-250, TAF250/230, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, Noninsulin-dependent diabetes mellitus, Crude Mortality, Adult-Onset, shortened, Gene Expression, TAFII250, Mortality, MDDGA6, Diseases, Kenny, Genetic Materials, cell nucleus, KIAA0609, Genetic Material, acetylglucosaminyltransferase-like 1A, Transcriptome Profiles, F14P3.4, Element, Factors, gyltl1b, mdc1d, Mortalities, Pancreatic Islets, Type 2, CG17603, TAF[[II]], LARGE_HUMAN, morbidity, early, Noninsulin-Dependent Diabetes Mellitus, type II, disease, wide, Semen, Crude Death Rate, DmelCG16910, Non-Insulin Dependent Diabetes, Islet Cell, SR3-5, Horka, p45, Fs(3)Horka, Cistron, short, Ovum, Ovum Donors, metal ion regulated proximal promoter sequence-specific DNA binding, other disease, cytoplasmic chromatin, d230, human being, Transcriptome Profile, FESTA-L, FESTA-S, Noninsulin Dependent, Mortality Declines, Gene, Coding, dTAFII250, Traits., Insulin B, broad, DIABETES MELLITUS TYPE 02, mortality measurement, EfW1, elavl2, froggy, Gyltl1a, Mortality Determinants, Crude, Translation, reduced, Homo sapiens, dmTAF1, Taf230, Non-Insulin-Dependent, non-insulin-dependent diabetes mellitus, DmF2, tiny, dmIKKgamma, IKK[[gamma]], Maturity-Onset Diabetes, TAF250, lod, T2DM, Taf200, Genetic, Medical Coding, Non-Insulin-Dependent Diabetes Mellitus, stubby, Islet Cells, Taf1p, LARGE, Maturity Onset Diabetes Mellitus, Age-Specific, Materials Translations, non-neoplastic, BPFD#36, Iletin, Maturity-onset diabetes mellitus, Noninsulin Dependent Diabetes Mellitus, IKK, Stable, Mortality Rates, mortality rate, disorder, Ketosis-Resistant, elements, TAF, Age Specific Death Rate, Diabetes, incidence, Controlled, Adult Onset, Type 2 diabetes, Morbidities, small, Controlling, TAF[[II]]250, Transcriptome, Adult-onset diabetes, Type 2 diabetes mellitus, HEL-N1, l(3)84Ab, medical condition, Nesidioblasts, Cistrons, RFXDC1, transcription factor activity, survival, Sodium Insulin, MTCHRS, p230, TFIID, atomus, Type 2 Diabetes Mellitus Non-Insulin Dependent, Gene Expression Signature, Determinants, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, KNOTTED1-like homeobox gene 5, Rates, Type 2 Diabetes, Exubera, TAF[[II]]230, xel-1, scale, Organ Donor, TAF[II]250, pathophysiology, Translatings, Age-Specific Death Rates, copper ion regulated core promoter proximal region sequence-specific binding, TRAITS, endemics, Langerhans Islets, DmelCG17603, Modern Man, Signature, Type II, Maturity Onset, mel-N1, glycosyltransferase-like protein LARGE1, TAF1"],"additional_accession":[]},"is_claimable":false,"name":"RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes","description":"A hallmark of type 2 diabetes (T2D), a major cause of world-wide morbidity and mortality, is dysfunction of insulin-producing pancreatic islet β cells. T2D genome-wide association studies (GWAS) have identified hundreds of signals, mostly in the non-coding genome and overlapping β cell regulatory elements, but translating these into biological mechanisms has been challenging. To identify early disease-driving events, we performed single cell spatial proteomics, sorted cell transcriptomics, and assessed islet physiology on pancreatic tissue from short-duration T2D and control donors. Here, through integrative analyses of these diverse modalities, we show that multiple gene regulatory modules are associated with early-stage T2D β cell-intrinsic defects. One notable example is the transcription factor RFX6, which we show is a highly connected β cell hub gene that is reduced in T2D and governs a gene regulatory network associated with insulin secretion defects and T2D GWAS variants. We validated the critical role of RFX6 in β cells through direct perturbation in primary human islets followed by physiological and single nucleus multiome profiling, which showed reduced dynamic insulin secretion and large-scale changes in the β cell transcriptome and chromatin accessibility landscape. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals and thus we anticipate this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits with GWAS data.","dates":{"updated":"2024-02-08 11:38:54"},"accession":"EGAS00001006273","cross_references":{"TAXONOMY":["9606"],"EGA":["EGAD00001008777","EGAC00001002684"]}}