title: TET2 Regulates Mast Cell Differentiation and Proliferation through Catalytic and Non-catalytic Activities.
abstract: Dioxygenases of the TET family impact genome functions by converting 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC). Here, we identified TET2 as a crucial regulator of mast cell differentiation and proliferation. In the absence of TET2, mast cells showed disrupted gene expression and altered genome-wide 5hmC deposition, especially at enhancers and in the proximity of downregulated genes. Impaired differentiation of Tet2-ablated cells could be relieved or further exacerbated by modulating the activity of other TET family members, and mechanistically it could be linked to the dysregulated expression of C/EBP family transcription factors. Conversely, the marked increase in proliferation induced by the loss of TET2 could be rescued exclusively by re-expression of wild-type or catalytically inactive TET2. Our data indicate that, in the absence of TET2, mast cell differentiation is under the control of compensatory mechanisms mediated by other TET family members, while proliferation is strictly dependent on TET2 expression.
authors.affiliation: Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), 6500 Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
authors.forename: Sara
authors.initials: S
authors.lastname: Montagner
authors.affiliation: Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), 6500 Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
authors.forename: Cristina
authors.initials: C
authors.lastname: Leoni
authors.affiliation: Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), 6500 Bellinzona, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Emming
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Della Chiara
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Balestrieri
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
authors.forename: Iros
authors.initials: I
authors.lastname: Barozzi
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Piccolo
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Togher
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA; School of Life Sciences, Ulsan National Institute of Science and Technology, UNIST-gil 50, Ulju-gun, Ulsan 689-798, Republic of Korea.
authors.forename: Myunggon
authors.initials: M
authors.lastname: Ko
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Natoli
authors.affiliation: Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), 6500 Bellinzona, Switzerland. Electronic address: silvia.monticelli@irb.usi.ch.
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticelli
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives / Q000378:metabolism; D001205:Ascorbic Acid / Q000494:pharmacology; D055162:Biocatalysis / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D049308:Dioxygenases; D017353:Gene Deletion; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D016678:Genome; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D014158:Transcription, Genetic
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D016207:Cytokines; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D049308:Dioxygenases; C551914:Tet2 protein, mouse; C551915:Tet3 protein, mouse; D001205:Ascorbic Acid
keywords: DNA hydroxymethylation; TET; differentiation; epigenetics; mast cells; proliferation