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Cell Rep. 2016 May 17;15(7):1566-1579. doi: 10.1016/j.celrep.2016.04.044. Epub 2016 May 5.

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

Author information

1
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.
2
Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy.
3
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
4
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.
5
Institute for Research in Biomedicine, Universita' della Svizzera italiana (USI), 6500 Bellinzona, Switzerland. Electronic address: silvia.monticelli@irb.usi.ch.

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.

KEYWORDS:

DNA hydroxymethylation; TET; differentiation; epigenetics; mast cells; proliferation

PMID:
27160912
PMCID:
PMC5584687
DOI:
10.1016/j.celrep.2016.04.044
[Indexed for MEDLINE]
Free PMC Article

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