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  • br Introduction Erythropoietin EPO is a glycoprotein

    2022-08-08


    Introduction Erythropoietin (EPO) is a glycoprotein hormone and the principal stimulator of erythropoiesis (Jelkmann, 2011). EPO promotes the proliferation and differentiation of red blood cells, which is important for oxygen transport. Low EPO levels in blood cause anemia; however, excessive levels of EPO cause polycythaemia. Therefore, it is important to accurately regulate EPO levels (Franke et al.,2013). In hypoxia, EPO is upregulated to adapt to the stressful environment (Haase, 2010). EPO production is controlled at the transcriptional level and is tightly regulated by hypoxia-inducible factors (HIFs) (Haase, 2013). HIFs are specific transcription factors that Apicidin sale are composed of an oxygen-sensitive α-subunit (HIF-α) and a constitutive β-subunit (HIF-β). In normoxia, the HIF-α subunit is rapidly hydroxylated by the prolyl hydroxylase domain (PHD) enzyme, whose activity is dependent on oxygen (Maxwell, 2005). The von Hippel–Lindau protein (pVHL) is a component of the multiprotein E3 ligase complex and leads to poly-ubiquitylation of the hydroxylated HIF-α subunit, which is destroyed by the proteasome (Maxwell, 2005). The HIF-α subunit is not hydroxylated and is thereby stabilized in hypoxia (Pugh and Ratcliffe, 2003). Therefore, the HIF-α subunit can translocate to the nucleus and heterodimerize with HIF-β subunits and then activate the transcription of hypoxic target genes, including EPO, upon binding to hypoxia response elements (HREs) (Yoon et al., 2011). EPO is mainly produced in the embryonic liver and adult kidney (Wenger and Hoogewijs, 2010). Several studies have indicated that EPO is mainly regulated by HIF-2α rather than HIF-1α in both the liver and kidney in hypoxia Kapitsinou et al.,2010; Rankin et al., 2007). EPO Apicidin sale is also regulated epigenetically, such as DNA methylation and histone post-translational modification (PTM) (Steinmann et al.,2011). Methylation in promoter and 5′-untranslated regions (5′-UTR) of the EPO gene represses the expression of EPO (Yin and Blanchard, 2000). Histone PTMs include acetylation, methylation, phosphorylation and ubiquitination, which can be associated with either gene activation or gene repression (Kouzarides, 2007). Histone acetylation is involved in the regulation of EPO expression (Rankin et al., 2007), and histone acetyltransferase (HAT) p300 plays a central role in co-activation in hypoxia-induced EPO (Wang et al., 2010). Whether other histone modifying enzymes, such as demethylase, are involved in the process remains unclear.
    Materials and methods
    Results
    Discussion Histone methylation is an important and widespread type of chromatin modification, which is known to influence many biological processes (Greer and Shi, 2012). Histone methylation is a reversible process catalyzed by methyltransferases and demethylases, which determines the precise regulation of gene expression (Dong and Weng, 2013). Di-methylation of lysine 9 of histone H3 (H3K9me2) is a characteristic mark of heterochromatin and transcriptional inhibition (Peters et al., 2003). Therefore, the demethylation of H3K9me2 can achieve transcriptional activation of specific gene. EPO was specifically expressed in embryonic liver and postnatal kidney, but not in other organs (Querbes et al.,2012). The pattern of EPO expression suggested that it is related to heterochromatin, in which formation and maintenance are often associated with specific histone PTMs (Hall et al.,2002). Histone methylation influences many biological processes in the context of development and cellular responses by controlling gene expression (Greer and Shi, 2012). H3K9 methylation is essential for heterochromatin formation and gene repression (Audergon et al.,2015). An important example is that fetal haemoglobin (HbF) gene expression also has developmental specificity, and its transcription is regulated by H3K9 methylation (Krivega et al., 2015). Accordingly, we proposed that H3K9 methylation may also be involved in EPO regulation.