TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities

Montagner, Sara; Leoni, Cristina; Emming, Stefan; Chiara, Giulia Della; Balestrieri, Chiara; Barozzi, Iros; Piccolo, Viviana; Togher, Susan; Ko, Myunggon; Rao, Anjana; Natoli, Gioacchino; Monticelli, Silvia

doi:10.1016/j.celrep.2017.08.011

Cited by 9 publications

(6 citation statements)

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“…Second, the differentially methylated regions identified in Dnmt3a-null cells showed substantial hyper-as well as hypomethylation at a variety of genomic regions, with very little correlation between changes in methylation and differential gene expression in the absence of Dnmt3a in both mouse and human cells (4,24,25). These observations suggest the existence of both direct and indirect effects due to the loss of Dnmt3a, and potentially also the existence of DNMT3A activities that are independent of its DNA catalytic activity (26), similar to what has been described for the catalytically inactive DNMT3L (27), some of the DNMT3B isoforms (28), and even for the TET family of DNA-modifying enzymes (29,30). To gain more insight into the mechanisms that may underlie increased mast cell responses in the absence of Dnmt3a, we therefore investigated global gene expression in WT and KO mast cells.…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Massupporting

confidence: 67%

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.DNA methylation | epigenetics | inflammation | mast cells

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Section: Dysregulated Dna Methylation Activity Leads To Increased Massupporting

confidence: 67%

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

114

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“…Consistent with our findings, a most recent study shows that TET2 binds to enhancers and facilitates transcription factor recruitment in hematopoietic cells ( 31 ). We cannot rule out at this point whether TET2 may function redundantly at promoter regions with other TET enzymes or may have catalytic-independent activities at these regions ( 32 ).…”

Section: Discussionmentioning

confidence: 99%

TET2 coactivates gene expression through demethylation of enhancers

et al. 2018

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“…In addition to the well-described catalytic activity of TET proteins, the preferential binding of TET proteins at 5mC-free promoters and their interaction with histone deacetylases, acetyltransferases, Polycomb repressive complex 2, and O-linked N-acetylglucosamine transferase to regulate gene expression 34,35 , suggest additional potential functions independent of its catalytic activity 36 . This possibility is supported by the demonstration that non-catalytic forms of TET are able to rescue the proliferative phenotype of Tet2 knockout cells 37 . Moreover, overexpression of TET1 or a catalytically inactive mutant in the mouse hippocampus results in the upregulation of several neuronal memory-associated genes 38 , further supporting non-conventional functions of TET proteins.…”

Section: Introductionmentioning

confidence: 94%

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn

et al. 2019

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Ten-eleven-translocation (TET) proteins catalyze DNA hydroxylation, playing an important role in demethylation of DNA in mammals. Remarkably, although hydroxymethylation levels are high in the mouse brain, the potential role of TET proteins in adult neurogenesis is unknown. We show here that a non-catalytic action of TET3 is essentially required for the maintenance of the neural stem cell (NSC) pool in the adult subventricular zone (SVZ) niche by preventing premature differentiation of NSCs into non-neurogenic astrocytes. This occurs through direct binding of TET3 to the paternal transcribed allele of the imprinted gene Small nuclear ribonucleoprotein-associated polypeptide N ( Snrpn) , contributing to transcriptional repression of the gene. The study also identifies BMP2 as an effector of the astrocytic terminal differentiation mediated by SNRPN. Our work describes a novel mechanism of control of an imprinted gene in the regulation of adult neurogenesis through an unconventional role of TET3.

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TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities

Abstract: Due to an error in Production, Table S6 was mistakenly duplicated and also appeared as Table S8 in the originally published version of this article. Table S8 has now been corrected online. The Production team regrets this error.

Cited by 9 publications

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Dnmt3a restrains mast cell inflammatory responses

Dnmt3a restrains mast cell inflammatory responses

TET2 coactivates gene expression through demethylation of enhancers

TET3 prevents terminal differentiation of adult NSCs by a non-catalytic action at Snrpn

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