Genome-wide analysis of histone modifications in human pancreatic islets
Open accessAbstract
The global diabetes epidemic poses a major challenge. Epigenetic events contribute to the etiology of diabetes; however, the lack of epigenomic analysis has limited the elucidation of the mechanistic basis for this link. To determine the epigenetic architecture of human pancreatic islets we mapped the genome-wide locations of four histone marks: three associated with gene activation—H3K4me1, H3K4me2, and H3K4me3—and one associated with gene repression, H3K27me3. Interestingly, the promoters of the highly transcribed insulin and glucagon genes are occupied only sparsely by H3K4me2 and H3K4me3. Globally, we identified important relationships between promoter structure, histone modification, and gene expression. We demonstrated co-occurrences of histone modifications including bivalent marks in mature islets. Furthermore, we found a set of promoters that is differentially modified between islets and other cell types. We also use our histone marks to determine which of the known diabetes-associated single-nucleotide polymorphisms are likely to be part of regulatory elements. Our global map of histone marks will serve as an important resource for understanding the epigenetic basis of type 2 diabetes.
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Studies of pancreatic islets from nondiabetic donors and patients with T2D have identified epigenetic modifications in genes that potentially affect β-cell function.
“Studies of pancreatic islets from nondiabetic donors ( 19 , 20 ) and patients with T2D ( 21 ) have identified epigenetic modifications in genes that potentially affect β-cell function.”
From β-Cell Failure in Type 2 Diabetes: Postulated Mechanisms and Prospects for Prevention and Treatment (2014) · cites this paper as [19]
The Abstract and Sample preparation and initial assessment sections report histone modifications in human islet genes, including PDX1 and insulin, consistent with potential effects on β-cell function. The Human islets section describes donor samples but does not state that the donors were nondiabetic. The T2D-patient portion of the citing sentence is attached to a different citation, not this paper. (LLM, conf=0.83)
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Epigenetic control of β-cell function and failure
Bernstein, D., Golson, M. L., & Kaestner, K. H. (2016) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2016.11.009 · Cited by 36 · see citing works
“In some cases, they occur because of changes in gene regulatory sequences, such as those that alter transcription factor binding of islet enhancers [92, 93] or which add CpGs that can contribute to gene silencing [94].”
Self-citationGerasimova, A. V., Chávez, L., Li, B., Seumois, G., Greenbaum, J., Rao, A., Vijayanand, P., & Peters, B. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054359 · Cited by 35 · see citing works
“Notably, the location of enhancers is highly cell-type specific [28], supporting the notion that different cell types maintain their specialized functions by selectively activating different regulatory regions of the genome [29].”
BackgroundThe metabolic-epigenetic nexus in type 2 diabetes mellitus
Davison, G. W., Irwin, R. E., & Walsh, C. P. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.12.025 · Cited by 35 · see citing works
Chromatin Regulators in Pancreas Development and Diabetes
Campbell, S. A., & Hoffman, B. G. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.12.005 · Cited by 34 · see citing works
Epigenetic regulation of inflammation: The metabolomics connection
Rath, S., Hawsawi, Y. M., Alzahrani, F. A., & Khan, M. I. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.09.008 · Cited by 34 · see citing works
Implication of epigenetics in pancreas development and disease
Quilichini, E., & Haumaître, C. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.10.010 · Cited by 34 · see citing works
Nutrients and the Pancreas: An Epigenetic Perspective
Weisbeck, A., & Jansen, R. J. (2017) · Nutrients · doi:10.3390/nu9030283 · Cited by 34 · see citing works
“Within human pancreatic islets cells, histone modifications have been associated with activation or repression of genes [70].”
BackgroundUncovering the gene regulatory network of type 2 diabetes through multi-omic data integration
Liu, J., Liu, S., Yu, Z.-M., Qiu, X.-R., Jiang, R., & Li, W.-Z. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03826-5 · Cited by 31 · see citing works
“The modification of H3K4me3 in pancreatic islets was confirmed to depend on the presence of CpG [20], which explains our result that CTCF binds near the chromatin region occupied by H3K4me3.”
Kuo, T., Damle, M., González, B. J., Egli, D. M., Lazar, M. A., & Accili, D. (2019) · JCI Insight · doi:10.1172/jci.insight.128351 · Cited by 32 · see citing works
Epigenetic regulation of pancreas development and function
Avrahami, D., & Kaestner, K. H. (2012) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2012.06.002 · Cited by 32 · see citing works
“The first genome-wide epigenetic studies of human pancreatic islets, using chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq analysis), focused on characterizing histone modifications that are involved in gene activation and repression such as H3K4me1, H3K4me2, H3K4me3, H3K79me2 and H3K27m…”
BackgroundSelf-citationThe Epigenome and Its Role in Diabetes
Waki, H., Yamauchi, T., & Kadowaki, T. (2012) · Current Diabetes Reports · doi:10.1007/s11892-012-0328-x · Cited by 31 · see citing works
“also conducted comprehensive epigenomic analyses in human pancreatic islets and showed that a substantial number of diabetes-associated non-coding SNPs are located in H3K4me1-enriched enhancer-like regions [95].”
Background“Omics” and “epi-omics” underlying the β-cell adaptation to insulin resistance
Jesus, D. F. D., & Kulkarni, R. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.06.003 · Cited by 33 · see citing works
“Furthermore, mature islets show bivalent histone markers and insulin and glucagon promoters show very low levels of H3K4me3 in contrast to genes like PDX1 and MAFB [49].”
BackgroundEpigenetic Regulation of β Cell Identity and Dysfunction
Sun, X., Wang, L., Obayomi, S. M. B., & Wei, Z. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.725131 · Cited by 32 · see citing works
Epigenetics and diabetic cardiomyopathy
Singh, G. B., Sharma, R., & Khullar, M. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2011.05.033 · Cited by 28 · see citing works
“Altered histone methylation patterns have been also observed to be associated with chromatin structure, gene expression in human pancreatic islets [30].”
BackgroundWarburton, A., Miyajima, F., Shazadi, K., Crossley, J., Johnson, M. R., Marson, A. G., Baker, G. A., Quinn, J. P., & Sills, G. J. (2015) · Epilepsy & Behavior · doi:10.1016/j.yebeh.2015.11.013 · Cited by 28 · see citing works
Epigenetic Modifications Associated with the Pathogenesis of Type 2 Diabetes Mellitus
Hossan, T., Kundu, S., Alam, S. S., & Nagarajan, S. (2019) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/1871530319666190301145545 · Cited by 30 · see citing works
Pancreatic progenitor epigenome maps prioritize type 2 diabetes risk genes with roles in development
Geusz, R. J., Wang, A., Chiou, J., Lancman, J. J., Wetton, N., Kefalopoulou, S., Wang, J., Qiu, Y., Yan, J., Aylward, A., et al. (2021) · eLife · doi:10.7554/elife.59067 · Cited by 26 · see citing works
Non-coding genome functions in diabetes
Cebola, I., & Pasquali, L. (2015) · Journal of Molecular Endocrinology · doi:10.1530/jme-15-0197 · Cited by 24 · see citing works
Moreno‐Asso, A., Castaño, C., Grilli, A., Novials, A., & Servitja, J. (2013) · Diabetologia · doi:10.1007/s00125-013-2930-0 · Cited by 23 · see citing works
“The identity of beta cells is defined during pancreatic development by epigenetic mechanisms that ensure the appropriate activation and repression of genes in beta cells [3–5].”
Epigenetics in β-cell adaptation and type 2 diabetes
Kim, H., & Kulkarni, R. (2020) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2020.10.008 · Cited by 22 · see citing works
Wang, L. Y., Wang, P., Li, M. J., Qin, J., Wang, X., Zhang, M. Q., & Wang, J. (2011) · Epigenetics · doi:10.4161/epi.6.12.18176 · Cited by 21 · see citing works
“19 Through the resulting network and heatmap pages, we observed several phenomena that were consistent with those reported in Bhandare et al. 19 First, all the four histone modification marks were significant in regulating gene expression (p < 0.05, Fig.”
InfluentialGenome-wide association study identifies novel type II diabetes risk loci in Jordan subpopulations
Dajani, R. B., Li, J., Wei, Z., March, M., Xia, Q., Khader, Y. S., Hakooz, N., Fatahallah, R., El-Khateeb, M. S., Arafat, A., et al. (2017) · PeerJ · doi:10.7717/peerj.3618 · Cited by 20 · see citing works
“3) and 267 additional T2D relevant cell lines (Supplementary Table 3) (Bhandare et al. 2010; Encode 268 Project Consortium 2012; Parker et al. 2013; Pasquali et al. 2014; Roadmap Epigenomics et al. 269 2015).”
BackgroundProfiling of Embryonic Stem Cell Differentiation
Shiraki, N., Ogaki, S., & Kume, S. (2014) · The Review of Diabetic Studies · doi:10.1900/rds.2014.11.102 · Cited by 19 · see citing works
“H3K27me3 is enriched in genes that are repressed by polycomb (PcG) proteins.”
BackgroundInfluentialDavid, S.-A., Piégu, B., Hennequet‐Antier, C., Pannetier, M., Aguirre-Lavin, T., Crochet, S., Bordeau, T., Couroussé, N., Brionne, A., Bigot, Y., et al. (2017) · Biological Procedures Online · doi:10.1186/s12575-017-0059-0 · Cited by 19 · see citing works
“Three regions were selected based on the literature, two of them known to be enriched for the H3K27me3 mark in myotubes and myoblasts (SOX2 and PAX5 [25]) and one known to display low levels of enrichment (GAPDH [27]).”
MethodNeuronal Lhx1 expression is regulated by DNMT1-dependent modulation of histone marks
Symmank, J., Bayer, C., Reichard, J., Pensold, D., & Zimmer‐Bensch, G. (2020) · Epigenetics · doi:10.1080/15592294.2020.1767372 · Cited by 18 · see citing works
“[35] Bhandare R, Schug J, Le Lay J, et al.”
BackgroundMethodNozaki, T., Yachie, N., Ogawa, R., Kratz, A., Saito, R., & Tomita, M. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-416 · Cited by 15 · see citing works
Salam, M. T. (2013) · Advances in experimental medicine and biology · doi:10.1007/978-1-4614-8603-9_11 · Cited by 15 · see citing works
Detection of type 2 diabetes related modules and genes based on epigenetic networks
Liu, H., Wang, T., Liu, H., Wei, Y., Zhao, G., Su, J., Wu, Q., Qiao, H., & Zhang, Y. (2014) · BMC Systems Biology · doi:10.1186/1752-0509-8-s1-s5 · Cited by 14 · see citing works
“A map of histone modifications for human islet tissue was constructed by ChIP-seqencing (ChIPseq), including the active (H3K4me1, H3K4me2 and H3K4me3) and inhibitive (H3K27me3) histone modifications, which was considered as the reference to the researches for the T2D etiology [18].”
BackgroundNovel Pancreatic Endocrine Maturation Pathways Identified by Genomic Profiling and Causal Reasoning
Gutteridge, A., Rukstalis, J. M., Ziemek, D., Tie, M., Ji, L., Ramos-Zayas, R., Nardone, N. A., Norquay, L. D., Brenner, M., Tang, K., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0056024 · Cited by 15 · see citing works
“Outside the context of directed differentiation, mature mammalian beta cells and islets have also been extensively profiled at the epigenetic [12–14], miRNA [15–17], protein [18] and gene expression levels [19–22].”
BackgroundAyan, E. B., & DeMi̇rci̇, H. (2022) · Current Diabetes Reviews · doi:10.2174/1573399819666220610150342 · Cited by 14 · see citing works
Mawla, A. M., van der Meulen, T., & Huising, M. O. (2023) · BMC Genomics · doi:10.1186/s12864-023-09293-6 · Cited by 14 · see citing works
“Previous studies have explored pancreatic islet cellular identity by evaluating epigenomic features such as methylation [12-14], histone modifications [15-18], and enhancer regulatory”
BackgroundEpigenetic Regulation of Pancreatic Islets
Haumaître, C. (2013) · Current Diabetes Reports · doi:10.1007/s11892-013-0403-y · Cited by 14 · see citing works
“Moreover, findings obtained with combination of DNaseand ChIP-seq approaches present a global map of the human islet epigenome and should provide functional context for noncoding variants emerging from genetic studies of diabetes and other islet disorders [20, 21].”
BackgroundEufrásio, A., Perrod, C., Ferreira, F. J., Duque, M., Galhardo, M., & Bessa, J. (2020) · Diabetes · doi:10.2337/db19-1049 · Cited by 13 · see citing works
Transcriptional and epigenetic regulation in human islets
Bramswig, N. C., & Kaestner, K. H. (2013) · Diabetologia · doi:10.1007/s00125-013-3150-3 · Cited by 12 · see citing works
“This technique was performed for the profiling of different histone modifications, such as H3K4me3, H3K27me3, H3K4me1 and H3K79me2, as well as CCCTC factor (CTCF) binding sites in whole human islets [22, 23].”
MethodSelf-citationTranscriptional Regulation of the Pancreatic Islet: Implications for Islet Function
Stitzel, M. L., Kycia, I., Kursawe, R., & Ucar, D. (2015) · Current Diabetes Reports · doi:10.1007/s11892-015-0635-0 · Cited by 13 · see citing works
“Data from multiple groups suggest that these promoters are not highly enriched for the typical punctate H3K4me3 active promoter mark despite the genes being highly expressed [39], [43], [47].”
InfluentialLam, V. K. L., Ronald, C. W., Lee, H. M., Hu, C., Park, K. S., Furuta, H., Wang, Y., Tam, C. H. T., Sim, X., Ng, D. P. K., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062378 · Cited by 11 · see citing works
“Regulation of gene expression (epigenetics) is a complex process involving chromatin and histone modifications which play pivotal roles in determining cellular structure and function [20,21,32].”
BackgroundOrganogenesis and functional genomics of the endocrine pancreas
Bramswig, N. C., & Kaestner, K. H. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0915-z · Cited by 12 · see citing works
“This allows for the identification of gene regulatory networks; for example, those that control development and function of the endocrine pancreas, and their epigenetic regulation [18, 19].”
BackgroundInfluentialSelf-citationLiang, X., Duan, H., Mao, Y., Koestner, U., Wei, Y., Deng, F. M., Zhuang, J., Li, H., Wang, C., Hernandez-Miranda, L. R., et al. (2021) · Diabetes · doi:10.2337/db20-0883 · Cited by 11 · see citing works
Skewed Epigenetics: An Alternative Therapeutic Option for Diabetes Complications
Togliatto, G., Dentelli, P., & Brizzi, M. F. (2015) · Journal of Diabetes Research · doi:10.1155/2015/373708 · Cited by 11 · see citing works
“In this sense, epigenomic analysis in human pancreatic islets shows a strict association with gene expression and histone modification and is possibly relevant to diabetes [77].”
mTORC1 is required for epigenetic silencing during β-cell functional maturation
Ni, Q., Sun, J., Wang, Y., Wang, Y., Liu, J., Ning, G., Wang, W., & Wang, Q. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101559 · Cited by 10 · see citing works
“A growing body of evidence suggests that epigenetic regulations, such as DNA methylation [10,33,34], histone modifications (H3K4me3 [35], H3K27me3 [23,25], HDACs [36]) and MicroRNAs [11], are tightly linked to b-cell identity and maturity.”
BackgroundEvidence for sequence biases associated with patterns of histone methylation
Wang, Z., & Willard, H. F. (2012) · BMC Genomics · doi:10.1186/1471-2164-13-367 · Cited by 11 · see citing works
“© 2012 Wang and Willard; licensee BioMed Ce Creative Commons Attribution License (http:/ distribution, and reproduction in any medium relate such maps to cellular phenotypes in organisms from yeast to human [9-11].”
BackgroundFunctional annotation of sixty-five type-2 diabetes risk SNPs and its application in risk prediction
Wu, Y., Jing, R., Dong, Y., Kuang, Q., Li, Y., Huang, Z., Gan, W., Xue, Y., Li, M., & Li, M. (2017) · Scientific Reports · doi:10.1038/srep43709 · Cited by 11 · see citing works
Translational implications of the β-cell epigenome in diabetes mellitus
Johnson, J. S., & Evans‐Molina, C. (2014) · Translational research · doi:10.1016/j.trsl.2014.03.002 · Cited by 10 · see citing works
Association of epigenetic landscapes with heterogeneity and plasticity in pancreatic cancer
Manoukian, P., Kuhnen, L. C., van Laarhoven, H. W. M., & Bijlsma, M. F. (2024) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2024.104573 · Cited by 9 · see citing works
Lv, J., Qiao, H., Liu, H., Wu, X., Zhu, J., Su, J., Wang, F., Cui, Y., & Zhang, Y. (2010) · PLoS ONE · doi:10.1371/journal.pone.0014219 · Cited by 9 · see citing works
“In addition, advances in experimental approaches have enabled high-throughput sequencing and genome wide studies to identify epigenetically regulated patterns [26–32].”
BackgroundJiang, C. H., Hu, Y., Wang, S., & Chen, C. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1145067 · Cited by 9 · see citing works
“The epigenetic events would contribute to and investigate the underlying mechanisms of the pathogenesis of diabetes (25).”
BackgroundEpigenetic Alterations Are Associated With Gastric Emptying Disturbances in Diabetes Mellitus
Narayanan, S. P., Lee, J., Bhagwate, A. V., Kuwelker, S., Yan, H., Ördög, T., & Bharucha, A. E. (2020) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000136 · Cited by 7 · see citing works
Current approaches in CRISPR-Cas systems for diabetes
Arivarasan, V. K., Diwakar, D., Kamarudheen, N., & Karthik, L. (2024) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2024.08.002 · Cited by 6 · see citing works
Human aging in the post-GWAS era: further insights reveal potential regulatory variants
Haider, S. A., & Faisal, M. (2015) · Biogerontology · doi:10.1007/s10522-015-9575-y · Cited by 5 · see citing works
“2009) suggesting that different cells selectively activate particular regulatory regions of the genome in order to maintain their integrity (Bhandare et al. 2010).”
BackgroundLiver kinase B1 ( LKB1 ) regulates the epigenetic landscape of mouse pancreatic beta cells
Haberman, N., Cheung, R., Pizza, G., Cvetešić, N., Nagy, D., Maude, H., Blázquez, L., Lenhard, B., Cebola, I., Rutter, G. A., et al. (2024) · The FASEB Journal · doi:10.1096/fj.202401078r · Cited by 4 · see citing works
“28 In healthy human islets, only a minority of genes carry both marks simultaneously, including those associated with neuronal TFs. 63 Our previous work 6 demonstrated the loss of β - cell identity and increased expression in neuronal genes in LKB1 β KO islets.”
Shared genetic contribution to type 1 and type 2 diabetes riskPreprint
Aylward, A., Chiou, J., Okino, M.-L., Kadakia, N., & Gaulton, K. J. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/285304 · Cited by 4 · see citing works
Implications of noncoding regulatory functions in the development of insulinomas
Ramos-Rodríguez, M., Subirana-Granés, M., Norris, R., Sordi, V., Fernández, Á., Fuentes-Páez, G., Pérez-González, B., Balaguer, C. B., Raurell‐Vila, H., Chowdhury, M., et al. (2024) · Cell Genomics · doi:10.1016/j.xgen.2024.100604 · Cited by 3 · see citing works
“It is worth noting that the genomic distribution of the mutations may be driven by the tissue-specific chromatin landscape of the tumoral cell type of origin 37,38 and may not represent the result of a tu-moral-driven positive selection process.”
BackgroundCreating new β cells: cellular transmutation by genomic alchemy
Moss, L. G. (2013) · Journal of Clinical Investigation · doi:10.1172/jci68348 · Cited by 2 · see citing works
“Major inroads have been made into characterizing the transcriptional regulatory landscape of the genome in the context of whole islets (11–13).”
Epigenetic Modifications and Type 2 Diabetes in Humans
Ling, C. (2014) · Frontiers in diabetes · doi:10.1159/000362470 · Cited by 2 · see citing works
- Authors
- Bhandare, R., Schug, J., Le Lay, J., Fox, A., Smirnova, O., Liu, C., Naji, A., & Kaestner, K. H.
- Affiliations
- University of Pennsylvania (US)
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2010-02-24
- Volume
- 20
- Issue
- 4
- Pages
- 428-433
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC2847745
- OpenAlex
- W2149952464
- Cited by
- 136
- References
- 27
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 4 · 2023: 19 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 5 · 2018: 3 · 2017: 11 · 2016: 3 · 2015: 12 · 2014: 14 · 2013: 17 · 2012: 13
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- University of Pennsylvania
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, DK R01-055342, R01DK055342, U01DK070430, P30DK019525)
- National Center for Research Resources (U42RR016600)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- histone modifications, pancreatic islets, type 2 diabetes, epigenetics, H3K4me1, H3K4me2, H3K4me3, H3K27me3, insulin gene, promoter structure, gene expression regulation, regulatory elements
- MeSH terms
- Histone Methyltransferases, Diabetes Mellitus, Type 2, Histones, Humans, Islets of Langerhans, Methylation, Promoter Regions, Genetic, Histone-Lysine N-Methyltransferase, Protein Processing, Post-Translational, Transcriptional Activation, CpG Islands, Polymorphism, Single Nucleotide, Gene Expression Profiling, Epigenesis, Genetic, Validation Studies as Topic, Genome-Wide Association Study
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