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Vitamin C and Somatic Cell Reprogramming
Published in Qi Chen, Margreet C.M. Vissers, Cancer and Vitamin C, 2020
Histone demethylases were initially proposed to be the key effectors of iPSC reprogramming in response to vitamin C treatment. Vitamin C is required for the optimal activity and demethylation capacity of several JHDMs [26], which include over 20 α-KGDDs in humans that hydroxylate and remove mono-, di-, or trimethyl-lysine marks in histones [27]. Histone demethylation is catalyzed by the JmjC domain to produce a highly reactive oxoferryl species that hydroxylates the methylated substrate, allowing spontaneous loss of the methyl group as formaldehyde [28]. Targeting lysines in the core histone H3, JHDM1 (Jhdm1a/b, KDM2) specifically demethylates H3K36; JHDM2A (JMJD1A, KDM3A) demethylates H3K9; JHDM3A (JMJD2A, KDM4) demethylates both trimethylated H3K9 and H3K36, and UTX (KDM6A) demethylates H3K27, all of which can be modulated by vitamin C to regulate chromatin state and gene expression [25,27,29,30].
The Epigenetic Role of Vitamin C in Neurological Development and Disease
Published in Qi Chen, Margreet C.M. Vissers, Vitamin C, 2020
Vitamin C may also be critical for maintaining histone methylation dynamics. JmjC domain-containing histone lysine demethylases (KDMs) are the largest enzyme family responsible for histone demethylation and are also members of the Fe(II) and 2OG-dependent dioxygenase superfamily [15]. KDMs are grouped into seven subfamilies based on sequence conservation and the methylated lysine residues that they antagonize. Containing nearly 20 members in total, KDMs are able to recognize and alter the methylation states of all histone lysine residues in order to drive downstream effects that are relevant to both health and disease [16]. KDMs are known to be critical for processes involved in development and mammalian disease states: For instance, JARID2 is known to associate with the Polycomb complex in embryonic stem cells (ESCs) and is essential for ESC differentiation, while KDM3A is critical for mouse spermatogenesis and is implicated in both fertility and obesity [17–19]. The importance of KDMs is wide reaching, and the role of vitamin C in sustaining their activity in critical physiologic processes is becoming more apparent. Vitamin C has been demonstrated to optimize the activity of KDM2, induce KDM-mediated somatic reprogramming, trigger embryonic stem cell demethylation, and alter global DNA and histone methylation to ensure oocyte maturation and developmental competence [20–23]. The role of vitamin C in propagating both DNA and histone demethylation may have a potentially widespread impact on numerous developmental processes and disease states, especially those regarding the nervous system, since neuronal cells contain one of the highest concentrations of intracellular vitamin C [24]. Histone and DNA methylation dynamics underlie nearly every neurological function and disease; thus, the epigenetic role of vitamin C in neural development and pathology deserves elucidation and speculation.
Targeting transcription factors in multiple myeloma: evolving therapeutic strategies
Published in Expert Opinion on Investigational Drugs, 2019
Shirong Li, Sonia Vallet, Antonio Sacco, Aldo Roccaro, Suzanne Lentzsch, Klaus Podar
Histone methylation and demethylation is regulated by either histone methyltransferases (HMTs): protein arginine methyltransferases, PRMT; SET- domain containing proteins; and DOT1 like histone lysine methyltransferase (DOT1L); or (lysine) histone demethylases (KDMs): lysine- specific demethylase (LSD) family, and the Jumonji C (JMJC) family, respectively. Histone methylation occurs at lysines, histidins, and arginins. Gene expression status is dependent on the methylation site. For example, H3K9me1 confers gene activation, H3K9me3 gene repression. Deregulated histone methylation modifiers in MM include MMSET, KDM3A (JMJD1A/JHDM2A), KDM6A (UTX), KDM6B, EZH2, as well as PRMT5 (Figure 5).
Adipose Tissue Macrophage-Mediated Inflammation in Obesity: A Link to Posttranslational Modification
Published in Immunological Investigations, 2023
Dongqin Wei, Xin Tian, Xiangyun Zhai, Chao Sun
When the STAT family regulates transcription, it rapidly recruits receptors bound to the cell membrane from the cytoplasm, is phosphorylated by tyrosine mediated by JAK, and is transferred to the nucleus (Mota de Sá et al. 2017). In the nucleus, STATs bind to DNA and regulate the transcription of target genes (Mota de Sá et al. 2017), where STATs are regulated by acetylation. This acetylation depends on the balance between HDACs and HATs (such as CBP). In cytokine activation of STAT3 transcription, CBP/p300 acetylates STAT3 on Lys 685, enhancing its DNA binding and transactivation activity. Mutations at this site impair STAT3 transcription. In contrast, HDACs (HDAC3, HDAC1, and HDAC2) promote STAT3 deacetylation and inhibit the transcription of STAT3 target genes (Zhuang 2013). However, unlike acetylation, methylation of STAT3 is a negative regulatory event. STAT3 is methylated by the H3K4 methyltransferase SET9 on K140 to enhance transcription (Yang et al. 2010). The JAK-STAT3 axis is also regulated by demethylase. Studies on cancer cells indicate that KDM3A is phosphorylated by JAK, and phosphorylated KDM3A reduces the level of H3K9me2 to activate STAT3 transcription (Kim et al. 2018). Similar to the transcriptional activation of STAT3, cytokines (such as IL4) bind to its receptor to activate JAK1/3 and phosphorylate STAT6. Phosphorylated STAT6 is transferred to the nucleus, where it undergoes acetylation or methylation modification to regulate transcription (Liu et al. 2012; Zhuang 2013). Yu et al. (2019) found that STAT6 Lys 383 was acetylated by CBP during the activation of macrophages, thereby inhibiting the M2 polarization of macrophages. These results indicate that PTM is an important link in controlling transduction in the JAK-STAT pathway. Research on the regulation of STAT signaling in macrophages by methylation modification is relatively weak, and some results have only been found in tumor cells. Whether these effects exist in ATMs remains to be further confirmed.