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

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.

A Histone Methyltransferase ESET Is Critical for T Cell Development

“…Different from the ChIP result in the previous report (47), our ChIP-Seq experiment revealed that H3K9me3 profile of the Fcgr2b gene was not altered by ESET deficiency (Supplemental Fig. 3C), indicating that Fcgr2b is not a direct target gene of ESET.…”

“…Very recently, the other group reported the effect of ESET (KMT1E) on T cell development by using the same lck-Cremediated T cell-specific ESET-deficient mice (47). They observed similar inhibition of T cell development and aberrant expression of Fcgr2b; however, their conclusion was totally different from ours.…”

“…They observed similar inhibition of T cell development and aberrant expression of Fcgr2b; however, their conclusion was totally different from ours. They demonstrated increased ZAP70 phosphorylation, CD69 upregulation, and caspase 3 cleavage upon TCR stimulation, concluding that augmented TCR signaling disturbed normal thymic selection, thus leading to thymocyte cell death (47). In our …”

Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers

“…The exact role of each mechanism is, however, still a matter of debate, different studies suggesting a more generalized role for SETDB1 in differentiated cells such as lymphocytes [14,15]. In mice, SETDB1 was shown to ensure Th2 cell stability by repressing ERVs that control the Th1 gene network [15], and also to repress the expression of FcγR-IIb in T cells, an inhibitory Fc receptor regulating the signaling through the TCR complex [16]. Accordingly, SETDB1 knock out induces an increased phosphorylation of ZAP70 in response to CD3 agonism, resulting in an increased cell activation and death at early thymic selection stage.…”

Retrotransposon derepression leads to activation of the unfolded protein response and apoptosis in pro-B cells

“…S5C,D). Interestingly, Fcgr2b is also upregulated in Setdb1-deficient T cells (Martin et al, 2015), although it remains to be determined if derepression of MLV1 can be observed in this context. RT-qPCR analyses for another MLV element (MLV5) similarly revealed strong derepression of the corresponding MLV transcript and upregulation of the neighboring gene (Fig.…”