Epigenetic dosage identifies two major and functionally distinct β cell subtypes

Dror, Erez; Fagnocchi, Luca; Wegert, Vanessa; Apostle, Stefanos; Grimaldi, Brooke; Gruber, Tim; Panzeri, Ilaria; Heyne, Steffen; Höffler, Kira Daniela; Kreiner, Victor; Ching, Reagan W.; Lu, Tess Tsai-Hsiu; Semwal, Ayush; Johnson, Ben K.; Senapati, Parijat; Lempradl, Adelheid; Schones, Dustin E.; Imhof, Axel; Shen, Hui; Pospisilik, J. Andrew

doi:10.1016/j.cmet.2023.03.008

Cited by 21 publications

(27 citation statements)

References 84 publications

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“…We also observe heterogeneity between beta cells at the level of the histone modification, H3K27me3, as recently documented [11], and find that NNATbeta cells in the adult are more likely to be marked by this repressive epigenetic modification. This again suggests there may be at least a partial overlap with the "bHI" population described in [11]. Might these findings be relevant for the pathogenesis of type 2 diabetes?…”

Section: Discussionsupporting

confidence: 85%

“…Interestingly, both embryonic and adult NNAT + beta cells were enriched for Npy and adult NNAT + beta cells had lower UCN3 protein, suggesting that these cells were not fully matured. NNAT + beta cells however had significantly higher insulin content, suggesting a possible, at least partial, overlap with the recently-described "CD63 hi " population recently defined by [29], and the "bHI" population described by [11].…”

Section: Discussionmentioning

confidence: 62%

“…Previous studies have provided an understanding of the transcriptional machinery that orchestrates beta cell development from early pancreatic and endocrine precursors [3,4]. To bolster these transcriptional programmes in vivo, chronic regulation via the epigenome appears to step in to maintain beta cell identity in the long term [5][6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Early reports [12][13][14], and more recent studies based on single cell transcriptomic profiling [15][16][17], electrophysiology [18] and functional imaging [19][20][21][22] have demonstrated functional heterogeneity amongst individual beta cells (reviewed in [23,24]). Identified subpopulations have been associated with known markers or maturation states (Flattop/Cfap126 [21], PSA-NCAM [25], CD81 [26], CD24 [11,27], TH [10], NPY [28], CD63 [29]), are 'virgin' beta cells [30] or are defined by their roles in coordinating islet-wide Ca 2+ dynamics (e.g. 'hubs' [19], 'leaders' [20] [31] and 'first responders' [32]).…”

Section: Introductionmentioning

confidence: 99%

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Differential CpG methylation atNnatin the early establishment of beta cell heterogeneity

Yong

Chen

et al. 2023

Preprint

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Beta cells within the pancreatic islet represent a heterogenous population wherein individual sub-groups of cells make distinct contributions to the overall control of insulin secretion. The molecular mechanisms through which beta cell hierarchy is established remain poorly understood. The neuronatin (Nnat) gene is imprinted in mice and humans and is required for normal insulin synthesis and secretion. Here, we demonstrate that Nnat is differentially expressed in a discrete beta cell population in a developmental-stage and DNA methylation (DNMT3A)-dependent manner. Explored in mice expressing eGFP from a bacterial artificial chromosome-expressed transgene, NNAT+cells displayed a discrete transcriptome, and appear to represent a beta cell population specialised for insulin production. Correspondingly, highly connected hub cells were less abundant in the NNAT+population. These findings demonstrate that differential DNA methylation at Nnat represents a novel means through which beta cell heterogeneity is established.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Differential CpG methylation atNnatin the early establishment of beta cell heterogeneity

Yong

Chen

et al. 2023

Preprint

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“…In addition, β-cell heterogeneity is also present at epigenetic levels, and two major subtypes with high and low H3K27me3 expression have been identi ed. [119] Importantly, β-cell heterogeneity could be altered in diabetes or under some stress conditions. [117,118] For example, among three β-cell clusters that vary in proliferative potential, the percentage of highly proliferative cells is signi cantly decreased in the presence of T2D.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes

Cui,

Feng,

Lei

et al. 2024

Chinese Medical Journal

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Pancreatic β-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing β-cells and hence restoring insulin production are gaining attention in translational diabetes research, and β-cell replenishment has been the main focus for diabetes treatment. Significant findings in β-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate β-cells. In this review, we summarize current knowledge on the mechanisms implicated in β-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to β-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting β-cell proliferation, inducing non-β-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for β-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous β-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

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Pancreatic β-cell heterogeneity in adult human islets and stem cell-derived islets

Aldous

Moin

Abdelalim

2023

Cell. Mol. Life Sci.

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Recent studies reported that pancreatic β-cells are heterogeneous in terms of their transcriptional profiles and their abilities for insulin secretion. Sub-populations of pancreatic β-cells have been identified based on the functionality and expression of specific surface markers. Under diabetes condition, β-cell identity is altered leading to different β-cell sub-populations. Furthermore, cell–cell contact between β-cells and other endocrine cells within the islet play an important role in regulating insulin secretion. This highlights the significance of generating a cell product derived from stem cells containing β-cells along with other major islet cells for treating patients with diabetes, instead of transplanting a purified population of β-cells. Another key question is how close in terms of heterogeneity are the islet cells derived from stem cells? In this review, we summarize the heterogeneity in islet cells of the adult pancreas and those generated from stem cells. In addition, we highlight the significance of this heterogeneity in health and disease conditions and how this can be used to design a stem cell-derived product for diabetes cell therapy.

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Epigenetic dosage identifies two major and functionally distinct β cell subtypes

Cited by 21 publications

References 84 publications

Differential CpG methylation atNnatin the early establishment of beta cell heterogeneity

Differential CpG methylation atNnatin the early establishment of beta cell heterogeneity

Pancreatic β-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes

Pancreatic β-cell heterogeneity in adult human islets and stem cell-derived islets

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