JMJD6 Protein, Human (His, StrepⅡ)

JMJD6 (N-term) is a dioxygenase that functions as both an arginine demethylase and a lysyl-hydroxylase. As a lysyl-hydroxylase, it catalyzes 5-hydroxylation of specific lysine residues in target proteins such as U2AF2/U2AF65 and LUC7L2, regulating RNA splicing by mediating 5-hydroxylation of U2AF2/U2AF65, thereby influencing its pre-mRNA splicing activity. The enzyme also hydroxylates its own N-terminus, which is essential for homooligomerization. JMJD6 plays a role in nucleolar liquid-liquid phase separation (LLPS) by post-translationally modifying LIAT1 at its lysine-rich domain, inhibiting LIAT1 nucleolar targeting (by similar). Beyond its peptidyl-lysine 5-dioxygenase activity, it may act as an RNA hydroxylase, binding single-stranded RNA. Additionally, JMJD6 serves as an arginine demethylase, preferentially targeting asymmetric dimethylation, and demethylates histone H3 at 'Arg-2' (H3R2me) and histone H4 at 'Arg-3' (H4R3me), including mono-, symmetric di-, and asymmetric dimethylated forms, contributing to the histone code. However, histone arginine demethylation may not be its primary in vivo activity. Collaborating with BRD4, JMJD6 interacts with the active positive transcription elongation factor b (P-TEFb) complex to regulate RNA polymerase II promoter-proximal pause release, activating transcription of numerous genes. At distal enhancers (anti-pause enhancers), it demethylates histone H4R3me2 and the methyl cap of 7SKsnRNA, leading to dissociation of the 7SKsnRNA:HEXIM1 inhibitory complex. Following repressive mark removal, the BRD4:JMJD6 complex recruits and retains P-TEFb on chromatin, promoting its activation, polymerase II pause release, and transcriptional activation. JMJD6 also demethylates other arginine-methylated proteins (e.g., ESR1) but lacks histone lysine demethylase activity. It is essential for embryonic differentiation of multiple organs and acts as a key regulator of hematopoietic differentiation (by similar), potentially influencing macrophage cytokine responses.