Original Article | Published:

KMT1E-mediated chromatin modifications at the FcγRIIb promoter regulate thymocyte development

Genes and Immunity volume 16, pages 162169 (2015) | Download Citation

Abstract

This work examines the role the lysine methyltransferase KMT1E (Setdb1) in thymocyte development. We have developed and described a T cell-specific conditional knockout of Setdb1. A partial block was seen at the double-positive to single-positive transition, causing reduced numbers of single-positive T cells in the thymus and periphery. Knockout thymocytes had reduced numbers of CD69+ and T-cell receptor TCRβ+ cells and increased numbers of apoptotic cells in the double-positive compartment, suggesting an alteration in the selection process. Transcriptional profiling of thymocytes revealed that Setdb1 deletion derepresses expression of FcγRIIb, the inhibitory Fc receptor. We demonstrate that a KMT1E-containing complex directly interacts with the FcγRIIb promoter and that histone H3 at lysine 9 tri-methylation at this promoter is dependent on Setdb1 expression. Derepression of FcγRIIb causes exacerbated signaling through the TCR complex, with specifically increased phosphorylation of ZAP70, affecting selection. This work identifies KMT1E as a novel repressor of FcγRIIb and identifies an underappreciated role of FcγRIIb in fine tuning thymocyte development.

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Author information

Affiliations

  1. Department of Ophthalmology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA

    • F J Martin
    • , Y Xu
    • , F Lohmann
    • , T B Nicholson
    • , J J Loureiro
    •  & Q Huang
  2. Abbvie Bioresearch Center, Immunology Early Discovery, Worcester, MA, USA

    • D N Ciccone
  3. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA

    • T Chen

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Competing interests

FJM, YX, FL, TBN, JJL and QH are employees of the Novartis Institutes of Biomedical Research.

DNC is an employee of AbbVie Inc. The remaining author declares no conflict of interest.

Corresponding author

Correspondence to Q Huang.

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DOI

https://doi.org/10.1038/gene.2014.70

Supplementary Information accompanies this paper on Genes and Immunity website (http://www.nature.com/gene)

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