Abstract
CXXC5 is a member of the zinc-finger CXXC family that binds to unmethylated CpG dinucleotides. CXXC5 modulates gene expressions resulting in diverse cellular events mediated by distinct signaling pathways. However, the mechanism responsible for CXXC5 expression remains largely unknown. We found here that of the 14 annotated CXXC5 transcripts with distinct 5′ untranslated regions encoding the same protein, transcript variant 2 with the highest expression level among variants represents the main transcript in cell models. The DNA segment in and at the immediate 5′-sequences of the first exon of variant 2 contains a core promoter within which multiple transcription start sites are present. Residing in a region with high G–C nucleotide content and CpG repeats, the core promoter is unmethylated, deficient in nucleosomes, and associated with active RNA polymerase-II. These findings suggest that a CpG island promoter drives CXXC5 expression. Promoter pull-down revealed the association of various transcription factors (TFs) and transcription co-regulatory proteins, as well as proteins involved in histone/chromatin, DNA, and RNA processing with the core promoter. Of the TFs, we verified that ELF1 and MAZ contribute to CXXC5 expression. Moreover, the first exon of variant 2 may contain a G-quadruplex forming region that could modulate CXXC5 expression.
Highlights
CXXC5 is a member of the zinc-finger CXXC family that binds to unmethylated CpG dinucleotides
Based on DNA sequence composition and motifs, chromatin configuration of as well as the presence of multiple transcriptional start sites (TSSs) together with an active RNA polymerase II at the core promoter, we suggest that a CpG islands (CGIs) promoter drives the expression of CXXC5
Based on DNA sequence composition and motifs, chromatin configuration of, and the presence of multiple TSSs together with an active PolII at the CXXC5 promoter, we suggest that a CGI promoter drives the expression of CXXC5
Summary
CXXC5 is a member of the zinc-finger CXXC family that binds to unmethylated CpG dinucleotides. Evidence indicates that morphogenic retinoic acid[11], multifunctional cytokine family member transforming growth factor-β12, bone morphogenetic protein 4 13,14, the Wnt family of secreted glycolipoprotein W nt3a15–17 or estrogen[18,19,20] alters the CXXC5 expression as the primary response gene, whose protein product subsequently leads to changes in cell type-specific secondary gene expressions[13,17,21,22,23,24,25,26] These changes are manifested as the modulation of cellular metabolism, proliferation, differentiation, or death in developmental processes and tissue maintenance[11,12,13,15,21,23,24,26,27,28,29,30,31]. Expressions of CXXC5 have been reported to correlate with the development of various pathologies including acute myeloid leukemia (AML), gastric, prostate, and breast c ancer[11,32,33,34,35,36,37,38]
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