Abstract
Type 2 diabetes mellitus (T2D), a major cause of worldwide morbidity and mortality, is characterized by dysfunction of insulin-producing pancreatic islet β cells1,2. T2D genome-wide association studies (GWAS) have identified hundreds of signals in non-coding and β cell regulatory genomic regions, but deciphering their biological mechanisms remains challenging3–5. Here, to identify early disease-driving events, we performed traditional and multiplexed pancreatic tissue imaging, sorted-islet cell transcriptomics and islet functional analysis of early-stage T2D and control donors. By integrating diverse modalities, we show that early-stage T2D is characterized by β cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk. After identifying the β cell hub gene and transcription factor RFX6 within one such module, we demonstrated multiple layers of genetic risk that converge on an RFX6-mediated network to reduce insulin secretion by β cells. RFX6 perturbation in primary human islet cells alters β cell chromatin architecture at regions enriched for T2D GWAS signals, and population-scale genetic analyses causally link genetically predicted reduced RFX6 expression with increased T2D risk. Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs and individuals, and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases or traits using GWAS data.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 621-629 |
| Number of pages | 9 |
| Journal | Nature |
| Volume | 624 |
| Issue number | 7992 |
| DOIs | |
| State | Published - Dec 21 2023 |
Funding
The authors thank the organ donors and their families for their invaluable donations and the International Institute for Advancement of Medicine (IIAM), Organ Procurement Organizations, National Disease Research Exchange (NDRI), and the Alberta Diabetes Institute IsletCore together with the Human Organ Procurement and Exchange (HOPE) program and Trillium Gift of Life Network (TGLN) for their partnership in studies of human pancreatic tissue for research. We thank J. Hughes, J. H. Jo, S. Kim, Y. Hang, J. Almaça, R. Stein and R. Haliyur for their valuable scientific insight regarding experimental design and methods. This study used human pancreatic islets that were provided by the NIDDK-funded Integrated Islet Distribution Program at the City of Hope (DK098085). This work was supported by the Human Islet Research Network (RRID:SCR_014393), the Human Pancreas Analysis Program (RRID:SCR_016202), DK106755, DK123716, DK123743, DK120456, DK104211, DK108120, DK104218, DK112232, DK112217, DK117960, DK126185, DK117147, HL142302, DK127084, HL163262, DK129469, DK135017, EY032442, T32GM007347, F30DK118830, DK020593 (Vanderbilt Diabetes Research and Training Center), The Leona M. and Harry B. Helmsley Charitable Trust, JDRF, Doris Duke Charitable Foundation, and the Department of Veterans Affairs (BX000666). Cell sorting was performed in the Vanderbilt Flow Cytometry Shared Resource (P30 CA068485, DK058404) and whole-slide imaging was performed in the Islet and Pancreas Analysis Core of the Vanderbilt DRTC (DK020593). Authors A.C.P. and M.B. are principal investigators and D.C.S. and C.D. are co-investigators under the Human Pancreas Analysis Program. S.C.J.P. is a principal investigator in the Accelerating Medicines Partnership for Common Metabolic Diseases (AMP-CMD). The authors thank the organ donors and their families for their invaluable donations and the International Institute for Advancement of Medicine (IIAM), Organ Procurement Organizations, National Disease Research Exchange (NDRI), and the Alberta Diabetes Institute IsletCore together with the Human Organ Procurement and Exchange (HOPE) program and Trillium Gift of Life Network (TGLN) for their partnership in studies of human pancreatic tissue for research. We thank J. Hughes, J. H. Jo, S. Kim, Y. Hang, J. Almaça, R. Stein and R. Haliyur for their valuable scientific insight regarding experimental design and methods. This study used human pancreatic islets that were provided by the NIDDK-funded Integrated Islet Distribution Program at the City of Hope (DK098085). This work was supported by the Human Islet Research Network (RRID:SCR_014393), the Human Pancreas Analysis Program (RRID:SCR_016202), DK106755, DK123716, DK123743, DK120456, DK104211, DK108120, DK104218, DK112232, DK112217, DK117960, DK126185, DK117147, HL142302, DK127084, HL163262, DK129469, DK135017, EY032442, T32GM007347, F30DK118830, DK020593 (Vanderbilt Diabetes Research and Training Center), The Leona M. and Harry B. Helmsley Charitable Trust, JDRF, Doris Duke Charitable Foundation, and the Department of Veterans Affairs (BX000666). Cell sorting was performed in the Vanderbilt Flow Cytometry Shared Resource (P30 CA068485, DK058404) and whole-slide imaging was performed in the Islet and Pancreas Analysis Core of the Vanderbilt DRTC (DK020593). Authors A.C.P. and M.B. are principal investigators and D.C.S. and C.D. are co-investigators under the Human Pancreas Analysis Program. S.C.J.P. is a principal investigator in the Accelerating Medicines Partnership for Common Metabolic Diseases (AMP-CMD).
ASJC Scopus subject areas
- General
