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Functional importance of CXXC5 in E2-driven cellular proliferation

Razizadeh, Negin
17β-estradiol (E2) as the main circulating estrogen hormone has an important role in the regulation of various tissues including mammary tissue. E2 effects target tissue functions by binding to the nuclear receptors, ERα and β. ERs regulate the expression of target genes. Previous studies conducted in our laboratory indicate that one of these estrogen responsive genes is CXXC5 which is regulated by ERα. CXXC5 has a highly conserved zinc-finger CXXC domain, which makes it a member of zinc-finger CXXC domain protein family. The family binds to non-methylated CpG dinucleotides, specifically in CpG island promoters and alters gene expressions through their enzymatic activities for DNA methylation or epigenetic modifications. However, structural and functional properties of CXXC5 remains largely unknown. In an attempt to decipher the role of CXXC5 in E2-ERα mediated cellular events, we uncovered that CXXC5 do not have an intrinsic transcription activation or repression function but through binding to CpG dinucleotides regulates gene expressions distinctly and mutually modulated by E2 as well. This results in E2-driven cellular proliferation. We therefore suggest that CXXC5 as a CpG binder involves in the regulation of E2-mediated transcriptional activation or repression of genes culminating in the regulation of cellular proliferation.