The function and regulation of TET2 in innate immunity and inflammation
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Protein & Cell
REVIEW The function and regulation of TET2 in innate immunity and inflammation Boyi Cong1, Qian Zhang2, Xuetao Cao1,2,3& 1
Laboratory of Immunity and Inflammation, College of Life Sciences, Nankai University, Tianjin 300071, China National Key Laboratory of Medical Immunology, Institute of Immunology, Navy Military Medical University, Shanghai 200433, China 3 Department of Immunology, Center for Immunotherapy, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing 100005, China & Correspondence: [email protected] (X. Cao) Received July 7, 2020 Accepted September 15, 2020
ABSTRACT TET2, a member of ten-eleven translocation (TET) family as α-ketoglutarate- and Fe2+-dependent dioxygenase catalyzing the iterative oxidation of 5-methylcytosine (5mC), has been widely recognized to be an important regulator for normal hematopoiesis especially myelopoiesis. Mutation and dysregulation of TET2 contribute to the development of multiple hematological malignancies. Recent studies reveal that TET2 also plays an important role in innate immune homeostasis by promoting DNA demethylation or independent of its enzymatic activity. Here, we focus on the functions of TET2 in the initiation and resolution of inflammation through epigenetic regulation and signaling network. In addition, we highlight regulation of TET2 at various molecular levels as well as the correlated inflammatory diseases, which will provide the insight to intervene in the pathological process caused by TET2 dysregulation.
KEYWORDS TET2, innate immune response, DNA demethylation, inflammatory resolution, inflammatory diseases
INTRODUCTION Innate immune responses are critical in protecting the host from infection and injury, which are efficiently and timely regulated to maintain the immune homeostasis. Diverse epigenetic mechanisms, referring to dynamic regulation of DNA modifications, histone modifications, chromatin remodeling and non-coding RNAs (ncRNAs), are implicated in precise regulation of innate immune responses through
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establishing specific gene expression patterns especially at transcriptional and post-transcriptional levels (Zhang and Cao, 2019). As the most canonical epigenetic modification, DNA methylation occurs by transferring the methyl group onto 5-carbon of the cytosine to form 5-methylcytosine (5mC), which plays a vital role in transcriptional silencing and genome stability (Jones, 2012), and is of great importance for mammalian development (Jones, 2012; Smith and Meissner, 2013). Aberrant changes of DNA methylation is associated with various pathological diseases, such as cancer (Klutstein et al., 2016), obesity (Zhang et al., 2017a) and inflammatory autoimmune diseases (Meda et al., 2011). As the chromosomal translocation partner initailly found in leukemia, TET family members, TET1, TET2 and TET3, have been proved to be a key regulator for DNA demethylation owing to its dioxygenase activity. Specifically, TET enzyme oxidizes the methyl group of 5-methylcytosine (5mC) into 5-hydroxymethylcy
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