TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation

Campbell, Stephanie A.; McDonald, Cassandra; Krentz, Nicole A.J.; Lynn, Francis C.; Hoffman, Brad G.

doi:10.1016/j.celrep.2019.07.035

Cited by 12 publications

(18 citation statements)

References 83 publications

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“…Previously, we reported that loss of Dpy30 and H3K4 methylation from PDX1 + progenitors increased the proportion of CPA1 + acinar progenitors while NEUROG3 + endocrine progenitors were reduced, suggesting a role for H3K4 methylation in endocrine cell specification (Campbell et al, 2019). While loss of H3K4 trimethylation had a minimal effect on bulk acinar or endocrine cell gene expression, our data suggested a role for H3K4 trimethylation in transcriptional maintenance of highly expressed genes in the acinar lineage.…”

Section: H3k4 Trimethylation In Endocrine Cell Differentiation and Fusupporting

confidence: 47%

“…DPY30 is required for TrxG catalytic activity or H3K4 methylation without affecting complex formation or co-activator activity (Bertero et al, 2015;Haddad et al, 2018). Previously described Dpy30 flox/flox mice (Campbell et al, 2019) were bred to generate experimental Neurog3-Cre; Dpy30 flox/flox mice (hereafter known as Dpy30DN) and littermate Dpy30 flox/flox (Cre-negative) control mice. In Dpy30DN embryos, DPY30 staining was absent from endocrine cells detected with the panendocrine marker chromogranin A (CHGA) beginning at embryonic day 14.5 (E14.5) and at postnatal day 0 (P0), P7, P14 and P24 ( Figure 1A).…”

Section: H3k4 Trimethylation Is Lost Postnatally In Dpy30dn Isletsmentioning

confidence: 99%

“…Timed matings were used to determine embryonic stages and the morning of vaginal plug discovery was considered embryonic day 0.5 (E0.5). Previously generated Dpy30 flox/flox mice (Campbell et al, 2019) were crossed to Neurog3-Cre driver mice (Schonhoff et al, 2004) to obtain conditional deletion of Dpy30 exon 4 in endocrine progenitors. In all studies, knockout mice (Dpy30DN; Neurog3-Cre;…”

Section: Mouse Strains and Embryo Collectionmentioning

confidence: 99%

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H3K4 trimethylation is required for postnatal pancreatic endocrine cell functional maturation

Campbell

Bégin

McDonald

et al. 2020

Preprint

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SummaryDuring pancreas development, endocrine progenitors differentiate into the islet-cell subtypes, which undergo further functional maturation in postnatal islet development. In islet β-cells, genes involved in glucose-stimulated insulin secretion are activated and glucose exposure increases the insulin response as β-cells mature. Here, we investigated the role of H3K4 trimethylation in endocrine cell differentiation and functional maturation by disrupting TrxG complex histone methyltransferase activity in mouse endocrine progenitors. In the embryo, genetic inactivation of TrxG component Dpy30 in NEUROG3+ cells did not affect the number of endocrine progenitors or endocrine cell differentiation. H3K4 trimethylation was progressively lost in postnatal islets and the mice displayed elevated random and fasting glycemia, as well as impaired glucose tolerance by postnatal day 24. Although postnatal endocrine cell proportions were equivalent to controls, islet RNA-sequencing revealed a downregulation of genes involved in glucose-stimulated insulin secretion and an upregulation of immature β-cell genes. Comparison of histone modification enrichment profiles in NEUROG3+ endocrine progenitors and mature islets suggested that genes downregulated by loss of H3K4 trimethylation more frequently acquire active histone modifications during maturation. Taken together, these findings suggest that H3K4 trimethylation is required for the activation of genes involved in the functional maturation of pancreatic islet endocrine cells.

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Section: H3k4 Trimethylation In Endocrine Cell Differentiation and Fusupporting

confidence: 47%

Section: H3k4 Trimethylation Is Lost Postnatally In Dpy30dn Isletsmentioning

confidence: 99%

Section: Mouse Strains and Embryo Collectionmentioning

confidence: 99%

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H3K4 trimethylation is required for postnatal pancreatic endocrine cell functional maturation

Campbell

Bégin

McDonald

et al. 2020

Preprint

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“…For in vivo 5-ethynyl-2’-deoxyuridine (EdU) labeling, mice were injected intraperitoneally with 0.5 mg EdU (Carbosynth) twice per day for seven consecutive days, and pancreata were isolated one day after the final injection. EdU detection in tissue sections was performed as described previously 23 .…”

Section: Methodsmentioning

confidence: 99%

“…Mice harboring conditional alleles of Dpy30 (ref. 23 ) and Rosa26 mTmG/+ (Jax 007576) were crossed with Pdx1-CreER Tg/0 (Jax 024968) or Ins1 Cre /+ (Jax 026801) lines to generate β-cell-specific Dpy30 KO animals. At 8 weeks old, Pdx1CreER Tg/0 mice were administered 8 mg tamoxifen dissolved in 100 μL corn oil by oral gavage three times, with ~48 hours between administrations.…”

Section: Methodsmentioning

confidence: 99%

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

Vanderkruk

Maeshima

Pasula

et al. 2021

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SummaryHistone 3 lysine 4 trimethylation (H3K4me3) is associated with promoters of actively expressed genes, with genes important for cell identity frequently having exceptionally broad H3K4me3-enriched domains at their TSS. While H3K4 methylation is implicated in contributing to transcription, maintaining transcriptional stability, facilitating enhancer-promoter interactions, and preventing irreversible silencing, some studies suggest it has little functional impact. Therefore, the function of H3K4 methylation is not resolved. Insufficient insulin release by β-cells is the primary etiology in type 2 diabetes (T2D) and is associated with the loss of expression of genes essential to normal β-cell function. We find that H3K4me3 is reduced in islets from mouse models of diabetes and from human donors with T2D. Using a genetic mouse model to impair H3K4 methyltransferase activity of TrxG complexes, we find that reduction of H3K4 methylation significantly reduces insulin production and glucose-responsiveness and increases transcriptional entropy, indicative of a loss of β-cell maturity. Genes that are downregulated by reduction to H3K4 methylation are concordantly downregulated in T2D. Loss of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to β-cell function and/or in particular chromatin environments are specifically affected. While neither H3K4me3 nor H3K4me1 are strictly required for the expression of many genes, the expression of genes with critical roles in β-cell function becomes destabilized, with increased variance and decreased overall expression. Our data further suggests that, in absence of H3K4me3, promoter-associated H3K4me1 is sufficient to maintain expression. Together, these data implicate H3K4 methylation dysregulation as destabilizing β-cell gene expression and contributing to β-cell dysfunction in T2D.

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Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

et al. 2023

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Aims/hypothesis Beta cells control glucose homeostasis via regulated production and secretion of insulin. This function arises from a highly specialised gene expression programme that is established during development and then sustained, with limited flexibility, in terminally differentiated cells. Dysregulation of this programme is seen in type 2 diabetes but mechanisms that preserve gene expression or underlie its dysregulation in mature cells are not well resolved. This study investigated whether methylation of histone H3 lysine 4 (H3K4), a marker of gene promoters with unresolved functional importance, is necessary for the maintenance of mature beta cell function. Methods Beta cell function, gene expression and chromatin modifications were analysed in conditional Dpy30 knockout mice, in which H3K4 methyltransferase activity is impaired, and in a mouse model of diabetes. Results H3K4 methylation maintains expression of genes that are important for insulin biosynthesis and glucose responsiveness. Deficient methylation of H3K4 leads to a less active and more repressed epigenome profile that locally correlates with gene expression deficits but does not globally reduce gene expression. Instead, developmentally regulated genes and genes in weakly active or suppressed states particularly rely on H3K4 methylation. We further show that H3K4 trimethylation (H3K4me3) is reorganised in islets from the Leprdb/db mouse model of diabetes in favour of weakly active and disallowed genes at the expense of terminal beta cell markers with broad H3K4me3 peaks. Conclusions/interpretation Sustained methylation of H3K4 is critical for the maintenance of beta cell function. Redistribution of H3K4me3 is linked to gene expression changes that are implicated in diabetes pathology. Graphical abstract

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TrxG Complex Catalytic and Non-catalytic Activity Play Distinct Roles in Pancreas Progenitor Specification and Differentiation

Cited by 12 publications

References 83 publications

H3K4 trimethylation is required for postnatal pancreatic endocrine cell functional maturation

H3K4 trimethylation is required for postnatal pancreatic endocrine cell functional maturation

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

Methylation of histone H3 lysine 4 is required for maintenance of beta cell function in adult mice

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