Epigenetic regulation of inflammation by CxxC domain‐containing proteins*

Abstract

Epigenetic regulation of gene transcription in the immune system is important for proper control of protective and pathogenic inflammation. Aberrant epigenetic modifications are often associated with dysregulation of the immune cells, including lymphocytes and macrophages, leading to pathogenic inflammation and autoimmune diseases. Two classical epigenetic markers-histone modifications and DNA cytosine methylation, the latter is the 5 position of the cytosine base in the context of CpG dinucleotides-play multiple roles in the immune system. CxxC domain-containing proteins, which basically bind to the non-methylated CpG (i.e., epigenetic "readers"), often function as "writers" of the epigenetic markers via their catalytic domain within the proteins or by interacting with other epigenetic modifiers. We herein report the most recent advances in our understanding of the functions of CxxC domaincontaining proteins in the immune system and inflammation, mainly focusing on T cells and macrophages. K E Y W O R D S DNA methylation, helper T cells, ten-eleven translocation (TET) proteins, trithorax 2 | Cp G p G -B IND ING G ROUP: C X XC1 IN THE IMMUNE SYS TEM CXXC1, also known as CpG-binding protein (CGBP) or CFP1, was the first identified CpG-binding protein 6 and is essential F I G U R E 1 A schematic representation of the domain architecture for 12 mouse CxxC domain-containing proteins and TET2 lacking the CxxC domain. The proteins are centered at the CxxC domain and drawn according to scale with the number of amino acids in the protein. Note that the three CxxC domains are numbered 1-3 for MBD1. The domain annotation was based on previous reports. 16,20,30,93 Annotations for catalytic domains are shown close to the schematic depictions: SET, Su-(var)3-9, enhancer of zeste and trithorax domain; JmjC, Jumonji C domain; core catalytic region for methylcytosine dioxygenase; MTase, methyltransferase. Annotations for non-catalytic domains are indicated in a box: PHD, plant homeodomain; SID, SET1-interacting domain; AT hook, DNA-binding motif with preference for AT-rich regions; Bromo, bromodomain; F-box, F-box domain; MBD, methyl-CpG-binding domain; RFD, replication foci domain; BAH, bromo-adjacent homology. All sequences are from NCBI mouse protein database (https://www.ncbi.nlm.nih.gov/protein):

Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis

“…T cells that lack nuclear factor of activated T-cells 2 (NFAT2), encoded by the Nfatc1 gene, produce less IL-4, indicating that the TCR-dependent activation of NFAT2 plays a role in Th2 cell differentiation ( 28 ). Prolonged TCR signaling is proposed to enhance the pathogenicity of Th2 cells due to a lack of Klf2 gene reactivation ( 29 , 30 ).…”

Editorial: Epigenetics of the immune component of inflammation

“…The epigenetic genes are constitutively activated or deactivated in multiple immune-or nonimmune cells under inflammatory conditions and contribute to a variety of inflammatory diseases, such as rheumatoid arthritis (RA) [Yang et al, as well as diabetes (3), Ding et al], and cancers (4,5), etc. Inflammation often hijacks various epigenetic mechanisms to promote occurrence and development of these diseases (6,7). In turn, epigenetic modifications also mediate pathologic development of inflammation by regulating immune components in inflammatory microenvironments (8,9).…”

“…, as well as diabetes ( 3 ), Ding et al ], and cancers ( 4 , 5 ), etc. Inflammation often hijacks various epigenetic mechanisms to promote occurrence and development of these diseases ( 6 , 7 ). In turn, epigenetic modifications also mediate pathologic development of inflammation by regulating immune components in inflammatory microenvironments ( 8 , 9 ).…”

KDM2A Deficiency in the Liver Promotes Abnormal Liver Function and Potential Liver Damage

“…KDM2A is an important member of the JmjC domain histone demethylases. Traditionally, it catalyzes the demethylation of histone 3 lysine 36 (H3K36) and histone 3 lysine 4 (H3K4), thereby regulating important biological processes such as chromatin remodeling and cellular development [1,2]. In recent years, we and others discovered that Biomolecules 2023, 13, 1457 2 of 11 KDM2A also modifies non-histone proteins, such as β-Catenin and NF-κB, to regulate their stability and transcriptional activity, respectively [3,4].…”