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Article ; Online: Islet Epigenetic Impacts on β-Cell Identity and Function.

Golson, Maria L

Comprehensive Physiology

2021 Volume 11, Issue 3, Page(s) 1961–1978

Abstract: The development and maintenance of differentiation is vital to the function of mature cells. Terminal differentiation is achieved by locking in the expression of genes essential for the function of those cells. Gene expression and its memory through ... ...

Abstract	The development and maintenance of differentiation is vital to the function of mature cells. Terminal differentiation is achieved by locking in the expression of genes essential for the function of those cells. Gene expression and its memory through generations of cell division is controlled by transcription factors and a host of epigenetic marks. In type 2 diabetes, β cells have altered gene expression compared to controls, accompanied by altered chromatin marks. Mutations, diet, and environment can all disrupt the implementation and preservation of the distinctive β-cell transcriptional signature. Understanding of the full complement of genomic control in β cells is still nascent. This article describes the known effects of histone marks and variants, DNA methylation, how they are regulated in the β cell, and how they affect cell-fate specification, maintenance, and lineage propagation. © 2021 American Physiological Society. Compr Physiol 11:1-18, 2021.
MeSH term(s)	Cell Differentiation ; DNA Methylation ; Diabetes Mellitus, Type 2 ; Epigenesis, Genetic ; Histones/metabolism ; Humans
Chemical Substances	Histones
Language	English
Publishing date	2021-06-01
Publishing country	United States
Document type	Journal Article
ISSN	2040-4603
ISSN (online)	2040-4603
DOI	10.1002/cphy.c200004
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Article: The leptin receptor has no role in delta-cell control of beta-cell function in the mouse.

Zhang, Jia / Katada, Kay / Mosleh, Elham / Yuhas, Andrew / Peng, Guihong / Golson, Maria L

Frontiers in endocrinology

2023 Volume 14, Page(s) 1257671

Abstract: Introduction: Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Several mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) ...

Abstract	Introduction: Leptin inhibits insulin secretion from isolated islets from multiple species, but the cell type that mediates this process remains elusive. Several mouse models have been used to explore this question. Ablation of the leptin receptor (Lepr) throughout the pancreatic epithelium results in altered glucose homeostasis and ex vivo insulin secretion and Ca2+ dynamics. However, Lepr removal from neither alpha nor beta cells mimics this result. Moreover, scRNAseq data has revealed an enrichment of LEPR in human islet delta cells. Methods: We confirmed LEPR upregulation in human delta cells by performing RNAseq on fixed, sorted beta and delta cells. We then used a mouse model to test whether delta cells mediate the diminished glucose-stimulated insulin secretion in response to leptin. Results: Ablation of Lepr within mouse delta cells did not change glucose homeostasis or insulin secretion, whether mice were fed a chow or high-fat diet. We further show, using a publicly available scRNAseq dataset, that islet cells expressing Lepr lie within endothelial cell clusters. Conclusions: In mice, leptin does not influence beta-cell function through delta cells.
MeSH term(s)	Animals ; Humans ; Mice ; Glucose/metabolism ; Insulin/metabolism ; Leptin/metabolism ; Receptors, Leptin/genetics ; Receptors, Leptin/metabolism ; Signal Transduction
Chemical Substances	Glucose (IY9XDZ35W2) ; Insulin ; Leptin ; Receptors, Leptin ; leptin receptor, mouse ; LEPR protein, human
Language	English
Publishing date	2023-10-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2023.1257671
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Article: FOXM1 acts sexually dimorphically to regulate functional β-cell mass.

Peng, Guihong / Mosleh, Elham / Yuhas, Andrew / Katada, Kay / Cherry, Christopher / Golson, Maria L

bioRxiv : the preprint server for biology

2023

Abstract: The transcription factor FOXM1 regulates β-cell proliferation and insulin secretion. Our previous work demonstrates that expressing an activated form of FOXM1 (FOXM1*) in β cells increases β-cell proliferation and mass in aged male mice. Additionally, ... ...

Abstract	The transcription factor FOXM1 regulates β-cell proliferation and insulin secretion. Our previous work demonstrates that expressing an activated form of FOXM1 (FOXM1) in β cells increases β-cell proliferation and mass in aged male mice. Additionally, FOXM1 enhances β-cell function even in young mice, in which no β-cell mass elevation occurs. Here, we demonstrate that FOXM1 acts in a sexually dimorphic manner in the β cell. Expression of FOXM1* in female mouse β cells does not affect β-cell proliferation or glucose tolerance. Transduction of male but not female human islets with FOXM1* enhances insulin secretion in response to elevated glucose. Estrogen contributes to diabetes susceptibility differences between males and females, and the estrogen receptor (ER)α is the primary mediator of β-cell estrogen signaling. We show that FOXM1* can rescue impaired glucose tolerance in female mice with a pancreas-wide ERα deletion. Further, FOXM1 and ERα binding sites overlap with each other and with other β-cell-enriched transcription factors, including ISL1, PAX6, MAF, and GATA. These data indicate that FOMX1 and ERα cooperate to regulate β-cell function and suggest a general mechanism contributing to the lower incidence of diabetes observed in women.
Language	English
Publishing date	2023-01-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.01.12.523673
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Article ; Online: Epigenetics in formation, function, and failure of the endocrine pancreas.

Golson, Maria L / Kaestner, Klaus H

Molecular metabolism

2017 Volume 6, Issue 9, Page(s) 1066–1076

Abstract: Background: Epigenetics, in the broadest sense, governs all aspects of the life of any multicellular organism, as it controls how differentiated cells arrive at their unique phenotype during development and differentiation, despite having a uniform ( ... ...

Abstract	Background: Epigenetics, in the broadest sense, governs all aspects of the life of any multicellular organism, as it controls how differentiated cells arrive at their unique phenotype during development and differentiation, despite having a uniform (with some exceptions such as T-cells and germ cells) genetic make-up. The endocrine pancreas is no exception. Transcriptional regulators and epigenetic modifiers shape the differentiation of the five major endocrine cell types from their common precursor in the fetal pancreatic bud. Beyond their role in cell differentiation, interactions of the organism with the environment are also often encoded into permanent or semi-permanent epigenetic marks and affect cellular behavior and organismal health. Epigenetics is defined as any heritable - at least through one mitotic cell division - change in phenotype or trait that is not the result of a change in genomic DNA sequence, and it forms the basis that mediates the environmental impact on diabetes susceptibility and islet function. Scope of review: We will summarize the impact of epigenetic regulation on islet cell development, maturation, function, and pathophysiology. We will briefly recapitulate the major epigenetic marks and their relationship to gene activity, and outline novel strategies to employ targeted epigenetic modifications as a tool to improve islet cell function. Major conclusions: The improved understanding of the epigenetic underpinnings of islet cell differentiation, function and breakdown, as well as the development of innovative tools for their manipulation, is key to islet cell biology and the discovery of novel approaches to therapies for islet cell failure.
MeSH term(s)	Animals ; Cell Differentiation/genetics ; DNA Methylation/genetics ; Diabetes Mellitus/genetics ; Epigenesis, Genetic/genetics ; Epigenomics/methods ; Histones/genetics ; Humans ; Islets of Langerhans/metabolism ; Islets of Langerhans/physiology ; Pancreas/metabolism ; Phenotype ; RNA, Untranslated/genetics ; RNA, Untranslated/metabolism ; Regulatory Elements, Transcriptional/genetics ; Transcriptional Activation/genetics
Chemical Substances	Histones ; RNA, Untranslated
Language	English
Publishing date	2017-05-31
Publishing country	Germany
Document type	Journal Article ; Review
ISSN	2212-8778
ISSN (online)	2212-8778
DOI	10.1016/j.molmet.2017.05.015
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Article ; Online: Cell-Surface ZnT8 Antibody Prevents and Reverses Autoimmune Diabetes in Mice.

Kasinathan, Devi / Guo, Zheng / Sarver, Dylan C / Wong, G William / Yun, Shumei / Michels, Aaron W / Yu, Liping / Sona, Chandan / Poy, Matthew N / Golson, Maria L / Fu, Dax

Diabetes

2024 Volume 73, Issue 5, Page(s) 806–818

MeSH term(s)	Mice ; Animals ; Diabetes Mellitus, Type 1/metabolism ; Mice, Inbred NOD ; Islets of Langerhans/metabolism ; Autoantigens ; Insulin
Chemical Substances	Autoantigens ; Insulin
Language	English
Publishing date	2024-02-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db23-0568
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Article ; Online: Fox transcription factors: from development to disease.

Golson, Maria L / Kaestner, Klaus H

Development (Cambridge, England)

2016 Volume 143, Issue 24, Page(s) 4558–4570

Abstract: Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with ...

Abstract	Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development.
MeSH term(s)	Animals ; Cell Cycle/genetics ; Embryonic Development/genetics ; Energy Metabolism/genetics ; Forkhead Transcription Factors/genetics ; Humans
Chemical Substances	Forkhead Transcription Factors
Language	English
Publishing date	2016--15
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	90607-4
ISSN	1477-9129 ; 0950-1991
ISSN (online)	1477-9129
ISSN	0950-1991
DOI	10.1242/dev.112672
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Article ; Online: Epigenetic control of β-cell function and failure.

Bernstein, Diana / Golson, Maria L / Kaestner, Klaus H

Diabetes research and clinical practice

2016 Volume 123, Page(s) 24–36

Abstract: Type 2 diabetes is a highly heritable disease, but only ∼15% of this heritability can be explained by known genetic variant loci. In fact, body mass index is more predictive of diabetes than any of the common risk alleles identified by genome-wide ... ...

Abstract	Type 2 diabetes is a highly heritable disease, but only ∼15% of this heritability can be explained by known genetic variant loci. In fact, body mass index is more predictive of diabetes than any of the common risk alleles identified by genome-wide association studies. This discrepancy may be explained by epigenetic inheritance, whereby changes in gene regulation can be passed along to offspring. Epigenetic changes throughout an organism's lifetime, based on environmental factors such as chemical exposures, diet, physical activity, and age, can also affect gene expression and susceptibility to diabetes. Recently, novel genome-wide assays of epigenetic marks have resulted in a greater understanding of how genetics, epigenetics, and the environment interact in the development and inheritance of diabetes.
MeSH term(s)	Animals ; Blood Glucose/genetics ; Blood Glucose/metabolism ; Cell Differentiation/genetics ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Epigenesis, Genetic/physiology ; Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Inheritance Patterns ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/physiology
Chemical Substances	Blood Glucose
Language	English
Publishing date	2016-11-21
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	632523-3
ISSN	1872-8227 ; 0168-8227
ISSN (online)	1872-8227
ISSN	0168-8227
DOI	10.1016/j.diabres.2016.11.009
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Article ; Online: Cell-Surface Autoantibody Targets Zinc Transporter-8 (ZnT8) for In Vivo β-Cell Imaging and Islet-Specific Therapies.

Guo, Zheng / Kasinathan, Devi / Merriman, Chengfeng / Nakayama, Maki / Li, Hua / Li, Huilin / Xu, Cheng / Wong, G William / Yu, Liping / Golson, Maria L / Fu, Dax

Diabetes

2022 Volume 72, Issue 2, Page(s) 184–195

Abstract: Type 1 diabetes (T1D) is a disease in which autoimmune attacks are directed at the insulin-producing β-cell in the pancreatic islet. Autoantigens on the β-cell surface membrane are specific markers for molecular recognition and targets for engagement by ... ...

Abstract	Type 1 diabetes (T1D) is a disease in which autoimmune attacks are directed at the insulin-producing β-cell in the pancreatic islet. Autoantigens on the β-cell surface membrane are specific markers for molecular recognition and targets for engagement by autoreactive B lymphocytes, which produce islet cell surface autoantibody (ICSA) upon activation. We report the cloning of an ICSA (mAb43) that recognizes a major T1D autoantigen, ZnT8, with a subnanomolar binding affinity and conformation specificity. We demonstrate that cell-surface binding of mAb43 protects the extracellular epitope of ZnT8 against immunolabeling by serum ICSA from a patient with T1D. Furthermore, mAb43 exhibits in vitro and ex vivo specificity for islet cells, mirroring the exquisite specificity of islet autoimmunity in T1D. Systemic administration of mAb43 yields a pancreas-specific biodistribution in mice and islet homing of an mAb43-linked imaging payload through the pancreatic vasculature, thereby validating the in vivo specificity of mAb43. Identifying ZnT8 as a major antigenic target of ICSA allows for research into the molecular recognition and engagement of autoreactive B cells in the chronic phase of T1D progression. The in vivo islet specificity of mAb43 could be further exploited to develop in vivo imaging and islet-specific immunotherapies.
MeSH term(s)	Animals ; Mice ; Autoantibodies ; Autoantigens ; Diabetes Mellitus, Type 1/therapy ; Tissue Distribution
Chemical Substances	Autoantibodies ; Autoantigens ; zinc-binding protein ; Slc30a8 protein, mouse
Language	English
Publishing date	2022-12-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db22-0477
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Article ; Online: 3D chromatin maps of the human pancreas reveal lineage-specific regulatory architecture of T2D risk.

Su, Chun / Gao, Long / May, Catherine L / Pippin, James A / Boehm, Keith / Lee, Michelle / Liu, Chengyang / Pahl, Matthew C / Golson, Maria L / Naji, Ali / Grant, Struan F A / Wells, Andrew D / Kaestner, Klaus H

Cell metabolism

2022 Volume 34, Issue 9, Page(s) 1394–1409.e4

Abstract: Three-dimensional (3D) chromatin organization maps help dissect cell-type-specific gene regulatory programs. Furthermore, 3D chromatin maps contribute to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and ...

Abstract	Three-dimensional (3D) chromatin organization maps help dissect cell-type-specific gene regulatory programs. Furthermore, 3D chromatin maps contribute to elucidating the pathogenesis of complex genetic diseases by connecting distal regulatory regions and genetic risk variants to their respective target genes. To understand the cell-type-specific regulatory architecture of diabetes risk, we generated transcriptomic and 3D epigenomic profiles of human pancreatic acinar, alpha, and beta cells using single-cell RNA-seq, single-cell ATAC-seq, and high-resolution Hi-C of sorted cells. Comparisons of these profiles revealed differential A/B (open/closed) chromatin compartmentalization, chromatin looping, and transcriptional factor-mediated control of cell-type-specific gene regulatory programs. We identified a total of 4,750 putative causal-variant-to-target-gene pairs at 194 type 2 diabetes GWAS signals using pancreatic 3D chromatin maps. We found that the connections between candidate causal variants and their putative target effector genes are cell-type stratified and emphasize previously underappreciated roles for alpha and acinar cells in diabetes pathogenesis.
MeSH term(s)	Chromatin ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/pathology ; Gene Expression Regulation ; Humans ; Insulin-Secreting Cells/pathology ; Islets of Langerhans/pathology
Chemical Substances	Chromatin
Language	English
Publishing date	2022-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2022.08.014
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Article ; Online: Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits.

Lasconi, Chiara / Pahl, Matthew C / Pippin, James A / Su, Chun / Johnson, Matthew E / Chesi, Alessandra / Boehm, Keith / Manduchi, Elisabetta / Ou, Kristy / Golson, Maria L / Wells, Andrew D / Kaestner, Klaus H / Grant, Struan F A

Sleep

2022 Volume 45, Issue 8

Abstract: We investigated the potential role of sleep-trait associated genetic loci in conferring a degree of their effect via pancreatic α- and β-cells, given that both sleep disturbances and metabolic disorders, including type 2 diabetes and obesity, involve ... ...

Abstract	We investigated the potential role of sleep-trait associated genetic loci in conferring a degree of their effect via pancreatic α- and β-cells, given that both sleep disturbances and metabolic disorders, including type 2 diabetes and obesity, involve polygenic contributions and complex interactions. We determined genetic commonalities between sleep and metabolic disorders, conducting linkage disequilibrium genetic correlation analyses with publicly available GWAS summary statistics. Then we investigated possible enrichment of sleep-trait associated SNPs in promoter-interacting open chromatin regions within α- and β-cells, intersecting public GWAS reports with our own ATAC-seq and high-resolution promoter-focused Capture C data generated from both sorted human α-cells and an established human beta-cell line (EndoC-βH1). Finally, we identified putative effector genes physically interacting with sleep-trait associated variants in α- and EndoC-βH1cells running variant-to-gene mapping and establish pathways in which these genes are significantly involved. We observed that insomnia, short and long sleep-but not morningness-were significantly correlated with type 2 diabetes, obesity and other metabolic traits. Both the EndoC-βH1 and α-cells were enriched for insomnia loci (p = .01; p = .0076), short sleep loci (p = .017; p = .022) and morningness loci (p = 2.2 × 10-7; p = .0016), while the α-cells were also enriched for long sleep loci (p = .034). Utilizing our promoter contact data, we identified 63 putative effector genes in EndoC-βH1 and 76 putative effector genes in α-cells, with these genes showing significant enrichment for organonitrogen and organophosphate biosynthesis, phosphatidylinositol and phosphorylation, intracellular transport and signaling, stress responses and cell differentiation. Our data suggest that a subset of sleep-related loci confer their effects via cells in pancreatic islets.
MeSH term(s)	Chromosome Mapping ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Humans ; Islets of Langerhans/metabolism ; Obesity/metabolism ; Sleep ; Sleep Initiation and Maintenance Disorders/metabolism
Language	English
Publishing date	2022-05-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	424441-2
ISSN	1550-9109 ; 0161-8105
ISSN (online)	1550-9109
ISSN	0161-8105
DOI	10.1093/sleep/zsac109
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