Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function
Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be t...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
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2024
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| Online Access: | https://hdl.handle.net/10356/180091 |
| _version_ | 1826120084012138496 |
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| author | Hu, Ming Kim, Innah Morán, Ignasi Peng, Weicong Sun, Orien Bonnefond, Amélie Khamis, Amna Bonàs-Guarch, Sílvia Froguel, Philippe Rutter, Guy A. |
| author2 | Lee Kong Chian School of Medicine (LKCMedicine) |
| author_facet | Lee Kong Chian School of Medicine (LKCMedicine) Hu, Ming Kim, Innah Morán, Ignasi Peng, Weicong Sun, Orien Bonnefond, Amélie Khamis, Amna Bonàs-Guarch, Sílvia Froguel, Philippe Rutter, Guy A. |
| author_sort | Hu, Ming |
| collection | NTU |
| description | Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, we examined multiple variants that influence SLC30A8 allele-specific expression. Epigenomic mapping has previously identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighboring genes. Here, we show that deletion of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves glucose-stimulated insulin secretion. While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21, or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion. |
| first_indexed | 2024-10-01T05:10:26Z |
| format | Journal Article |
| id | ntu-10356/180091 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T05:10:26Z |
| publishDate | 2024 |
| record_format | dspace |
| spelling | ntu-10356/1800912024-09-22T15:38:11Z Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function Hu, Ming Kim, Innah Morán, Ignasi Peng, Weicong Sun, Orien Bonnefond, Amélie Khamis, Amna Bonàs-Guarch, Sílvia Froguel, Philippe Rutter, Guy A. Lee Kong Chian School of Medicine (LKCMedicine) Medicine, Health and Life Sciences Transcriptional regulation Risk variant Variants at the SLC30A8 locus are associated with type 2 diabetes (T2D) risk. The lead variant, rs13266634, encodes an amino acid change, Arg325Trp (R325W), at the C-terminus of the secretory granule-enriched zinc transporter, ZnT8. Although this protein-coding variant was previously thought to be the sole driver of T2D risk at this locus, recent studies have provided evidence for lowered expression of SLC30A8 mRNA in protective allele carriers. In the present study, we examined multiple variants that influence SLC30A8 allele-specific expression. Epigenomic mapping has previously identified an islet-selective enhancer cluster at the SLC30A8 locus, hosting multiple T2D risk and cASE associations, which is spatially associated with the SLC30A8 promoter and additional neighboring genes. Here, we show that deletion of variant-bearing enhancer regions using CRISPR-Cas9 in human-derived EndoC-βH3 cells lowers the expression of SLC30A8 and several neighboring genes and improves glucose-stimulated insulin secretion. While downregulation of SLC30A8 had no effect on beta cell survival, loss of UTP23, RAD21, or MED30 markedly reduced cell viability. Although eQTL or cASE analyses in human islets did not support the association between these additional genes and diabetes risk, the transcriptional regulator JQ1 lowered the expression of multiple genes at the SLC30A8 locus and enhanced stimulated insulin secretion. Published version G.A.R. was supported by a Wellcome Trust Investigator award (212625/Z/18/Z), UKRI-Medical Research Council (MRC) Programme grant (MR/R022259/1), an NIH-NIDDK project grant (R01DK135268), a CIHRJDRF Team grant (CIHR-IRSC TDP-186358 and JDRF 4-SRA-2023-1182-S-N), CRCHUM start-up funds, and an Innovation Canada John R. Evans Leader Award (CFI 42649). 2024-09-16T06:00:02Z 2024-09-16T06:00:02Z 2024 Journal Article Hu, M., Kim, I., Morán, I., Peng, W., Sun, O., Bonnefond, A., Khamis, A., Bonàs-Guarch, S., Froguel, P. & Rutter, G. A. (2024). Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function. The FASEB Journal, 38(8), e23610-. https://dx.doi.org/10.1096/fj.202301700RR 0892-6638 https://hdl.handle.net/10356/180091 10.1096/fj.202301700RR 38661000 2-s2.0-85191304662 8 38 e23610 en The FASEB Journal © 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. application/pdf |
| spellingShingle | Medicine, Health and Life Sciences Transcriptional regulation Risk variant Hu, Ming Kim, Innah Morán, Ignasi Peng, Weicong Sun, Orien Bonnefond, Amélie Khamis, Amna Bonàs-Guarch, Sílvia Froguel, Philippe Rutter, Guy A. Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function |
| title | Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function |
| title_full | Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function |
| title_fullStr | Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function |
| title_full_unstemmed | Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function |
| title_short | Multiple genetic variants at the SLC30A8 locus affect local super-enhancer activity and influence pancreatic β-cell survival and function |
| title_sort | multiple genetic variants at the slc30a8 locus affect local super enhancer activity and influence pancreatic β cell survival and function |
| topic | Medicine, Health and Life Sciences Transcriptional regulation Risk variant |
| url | https://hdl.handle.net/10356/180091 |
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