CXXC finger protein 1 is critical for T-cell intrathymic development through regulating H3K4 trimethylation

Abstract

T-cell development in the thymus is largely controlled by an epigenetic program, involving in both DNA methylation and histone modifications. Previous studies have identified Cxxc1 as a regulator of both cytosine methylation and histone 3 lysine 4 trimethylation (H3K4me3). However, it is unknown whether Cxxc1 plays a role in thymocyte development. Here we show that T-cell development in the thymus is severely impaired in Cxxc1-deficient mice. Furthermore, we identify genome-wide Cxxc1-binding sites and H3K4me3 modification sites in wild-type and Cxxc1-deficient thymocytes. Our results demonstrate that Cxxc1 directly controls the expression of key genes important for thymocyte survival such as RORγt and for T-cell receptor signalling including Zap70 and CD8, through maintaining the appropriate H3K4me3 on their promoters. Importantly, we show that RORγt, a direct target of Cxxc1, can rescue the survival defects in Cxxc1-deficient thymocytes. Our data strongly support a critical role of Cxxc1 in thymocyte development.

CFP1 Regulates Histone H3K4 Trimethylation and Developmental Potential in Mouse Oocytes

“…All mice used were handled with care and according to the Animal Research Committee guidelines of Zhejiang University. Cxxc1 fl/fl mouse strain has been engineered and described previously (Cao et al, 2016). Zp3-Cre transgenic mice were previously reported (Lewandoski et al, 1997).…”

Cxxc Finger Protein 1 Positively Regulates GM-CSF-Derived Macrophage Phagocytosis Through Csf2rα-Mediated Signaling

“…In CFP1 conditional knockout mice (Mx1 Cre), ablation of CFP1 results in a nearly complete loss of lineage-committed progenitors and mature cells after the induction of Cre expression in adult animals ( 23 ). To investigate the role of CFP1 in inflammatory macrophages, we crossed Cxxc1 -floxed mice ( Cxxc1 fl/fl ) ( 17 ) with LysM-Cre knock-in mice to delete CFP1 in neutrophils, monocytes, and macrophages. We performed qPCR and western blot analyses to detect the deficiency of CFP1 in GM-CSF-cultured bone marrow-derived macrophages, which confirmed that CFP1 was successfully deleted in the CFP1-deficient mice (Figures S1A,B in the Supplementary Material).…”

“…The Cxxc1 fl/fl mouse strain has been described previously ( 17 ). LysM-Cre mice (004781) were originally from the Jackson Laboratory.…”

“…CFP1-dependent H3K4me3 regulates H3K9 acetylation and histone acetyl transferase recruitment ( 16 ). Recent studies demonstrated that CFP1 plays a critical role in thymocyte development, and loss of CFP1 leads to a severe blockade of intrathymic T cell development ( 17 ). However, the role of CFP1-mediated H3K4me3 in macrophages remains unclear.…”

Identification of HeLa cell proteins that interact with Chlamydia�trachomatis glycogen synthase using yeast two‑hybrid assays

“…cFP1, an unmethylated cpG-binding protein, is a component of the mammalian set1 histone methyltransferase complex, which is involved in histone methylation, regulating T-cell development and promoting cellular differentiation (24). anti-chlamydial T cells may represent a double-edged sword, and may be responsible for initiating the pathological changes associated with chlamydial infection (25).…”