The zinc finger transcription factor PW1/PEG3 restrains murine beta cell cycling

Sojoodi, Mozhdeh; Stradiot, Leslie; Heremans, Yves; Leuckx, Gunter; Besson, V.; Staels, Willem; Casteele, Mark Van de; Marazzi, Giovanna; Sassoon, David; Heimberg, Henry; Bonfanti, Paola

doi:10.1007/s00125-016-3954-z

Cited by 6 publications

(9 citation statements)

References 27 publications

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“…We demonstrate further that Pw1 expressing adult stem/progenitor cells are characterized by the presence of sex steroid receptors. Consistent with this observation, the number of Pw1 expressing cells in the heart were shown to increase during pregnancy [ 90 ], while the pregnancy-induced expansion of pancreatic β-cells inversely correlates with the levels of Pw1 expression [ 41 ]. Accumulating evidence also demonstrates the interaction of sex hormones in stem cell behaviors.…”

Section: Discussionmentioning

confidence: 73%

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Paternally expressed gene 3 (Pw1/Peg3) promotes sexual dimorphism in metabolism and behavior

et al. 2022

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The paternally expressed gene 3 (Pw1/Peg3) is a mammalian-specific parentally imprinted gene expressed in stem/progenitor cells of the brain and endocrine tissues. Here, we compared phenotypic characteristics in Pw1/Peg3 deficient male and female mice. Our findings indicate that Pw1/Peg3 is a key player for the determination of sexual dimorphism in metabolism and behavior. Mice carrying a paternally inherited Pw1/Peg3 mutant allele manifested postnatal deficits in GH/IGF dependent growth before weaning, sex steroid dependent masculinization during puberty, and insulin dependent fat accumulation in adulthood. As a result, Pw1/Peg3 deficient mice develop a sex-dependent global shift of body metabolism towards accelerated adiposity, diabetic-like insulin resistance, and fatty liver. Furthermore, Pw1/Peg3 deficient males displayed reduced social dominance and competitiveness concomitant with alterations in the vasopressinergic architecture in the brain. This study demonstrates that Pw1/Peg3 provides an epigenetic context that promotes male-specific characteristics through sex steroid pathways during postnatal development.

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Section: Discussionmentioning

confidence: 73%

“…Paternal loss of Pw1 has been shown to lead to increased β-cells cycling in Pw1 +/pat- males at 3 months of age [ 41 ]. The increase of proliferation at a younger age may result in increased insulin production in later adulthood.…”

Section: Resultsmentioning

confidence: 99%

Paternally expressed gene 3 (Pw1/Peg3) promotes sexual dimorphism in metabolism and behavior

et al. 2022

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“…The transgenic PW1 reporter mouse model has facilitated the identification of PW1 + cells and demonstrated the importance of PW1 as a pan-tissue stem cell marker 19,20,[26][27][28] . Herein, we used this model to specifically isolate cardiac PW1 + cells and adopt a multi-omic unbiased approach to further decipher the cell surface membranome of these cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells

Bouvet

Claude

Roux

et al. 2020

Sci Rep

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There is currently no therapy to limit the development of cardiac fibrosis and consequent heart failure. We have recently shown that cardiac fibrosis post-myocardial infarction (MI) can be regulated by resident cardiac cells with a fibrogenic signature and identified by the expression of PW1 (Peg3). Here we identify αV-integrin (CD51) as an essential regulator of cardiac PW1 + cells fibrogenic behavior. We used transcriptomic and proteomic approaches to identify specific cell-surface markers for cardiac PW1 + cells and found that αV-integrin (CD51) was expressed in almost all cardiac PW1 + cells (93% ± 1%), predominantly as the αVβ1 complex. αV-integrin is a subunit member of the integrin family of cell adhesion receptors and was found to activate complex of latent transforming growth factor beta (TGFβ at the surface of cardiac PW1 + cells. Pharmacological inhibition of αV-integrin reduced the profibrotic action of cardiac PW1 + CD51 + cells and was associated with improved cardiac function and animal survival following MI coupled with a reduced infarct size and fibrotic lesion. These data identify a targetable pathway that regulates cardiac fibrosis in response to an ischemic injury and demonstrate that pharmacological inhibition of αV-integrin could reduce pathological outcomes following cardiac ischemia. Heart failure (HF) remains a leading cause of mortality and hospitalization worldwide and represents a heavy financial burden on health care systems 1-6. Current pharmacological treatments limit the peripheral consequences of cardiac dysfunction, but therapeutic approaches that impact primary adverse cardiac remodeling at the myocardial level are limited. While the etiology of HF is diverse, HF is typically associated with a range of physiological and morphological changes including fibrosis within the myocardium 7-9. Cardiac fibrosis is characterized with the excessive production and deposition of extracellular matrix (ECM) proteins within the myocardium that results in normal tissue architecture disruption, reduced tissue compliance, and mechanical and electrical dysfunction, consequently leading to HF 10,11. The mechanisms underlying cardiac fibrosis are incompletely understood, thereby impeding the development of effective anti-fibrotic therapeutics to complement the current therapies for HF 9,11,12. Activated cardiac fibroblasts are essential for the production of ECM proteins that accumulate during cardiac fibrosis; however, recent studies have established that cardiac fibroblasts represent a heterogeneous cell population 10-14. The exact nature of activated fibroblasts and consequently the sources of cardiac fibrosis remain unclear 9,12. Different mechanisms underlying fibrosis have been reported including the activation and

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“…Importantly, a significant number of imprinted genes play key functional roles in beta cells, both during their early development and in the adult [58]. These include regulation of insulin secretion (Nnat [59,60], Plagl1 (ZAC1) [57,61]), beta cell mass (Cdkn1c [62,63], Dlk1 [64], Peg3 [65], Grb10 [66,67], Rasgrf1 [68]) and epigenetic regulation (Gtl2 (MEG3) [69,70], H19 [71]) (Table 1). Interestingly, imprinted gene expression is deregulated in subclones of stable mouse-derived MIN6 beta cells that are "poorly responsive" in terms of insulin secretion to glucose and other secretagogues compared with "highly responsive" MIN6 subclones [72], and in pancreatic islets from T2D vs non-diabetic subjects [66,70,[73][74][75].…”

Section: Imprinted Genes and Pancreatic Beta Cellsmentioning

confidence: 99%

“…Imprinted genes play key functional roles in beta cells [57,[59][60][61][62][63][64][65][66][67][69][70][71] and a disproportionate number display deregulated expression in a model of diminished glucose-stimulated insulin secretion (GSIS) [72] and in pancreatic islets from T2D patients [66,70,[73][74][75]. Interestingly, overnutrition (high fat or high sugar diets) has been linked to long-term, programmed epigenetic changes in gene expression at imprinted loci in humans and rodents [124][125][126].…”

Section: Transcriptomic Diversity Between Beta Cell Subpopulationsmentioning

confidence: 99%

Importance of Both Imprinted Genes and Functional Heterogeneity in Pancreatic Beta Cells: Is There a Link?

Chabosseau

Rutter

Millership

2021

IJMS

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Diabetes mellitus now affects more than 400 million individuals worldwide, with significant impacts on the lives of those affected and associated socio-economic costs. Although defects in insulin secretion underlie all forms of the disease, the molecular mechanisms which drive them are still poorly understood. Subsets of specialised beta cells have, in recent years, been suggested to play critical roles in “pacing” overall islet activity. The molecular nature of these cells, the means through which their identity is established and the changes which may contribute to their functional demise and “loss of influence” in both type 1 and type 2 diabetes are largely unknown. Genomic imprinting involves the selective silencing of one of the two parental alleles through DNA methylation and modified imprinted gene expression is involved in a number of diseases. Loss of expression, or loss of imprinting, can be shown in mouse models to lead to defects in beta cell function and abnormal insulin secretion. In the present review we survey the evidence that altered expression of imprinted genes contribute to loss of beta cell function, the importance of beta cell heterogeneity in normal and disease states, and hypothesise whether there is a direct link between the two.

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The zinc finger transcription factor PW1/PEG3 restrains murine beta cell cycling

Cited by 6 publications

References 27 publications

Paternally expressed gene 3 (Pw1/Peg3) promotes sexual dimorphism in metabolism and behavior

Paternally expressed gene 3 (Pw1/Peg3) promotes sexual dimorphism in metabolism and behavior

Anti-integrin αv therapy improves cardiac fibrosis after myocardial infarction by blunting cardiac PW1+ stromal cells

Importance of Both Imprinted Genes and Functional Heterogeneity in Pancreatic Beta Cells: Is There a Link?

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