CTCF-KDM4A complex correlates with histone modifications that negatively regulate gene expression in cancer cell lines.

Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic modifications associated with gene silencing and RNA Polymerase II elongation, respectively. is abnormally expressed in cancer, affecting the expression of multiple targets, such as the gene. This enzyme localizes at the first intron of , and the dissociation of KDM4A increases gene expression. assays showed that KDM4A-mediated demethylation is enhanced in the presence of CTCF, suggesting that CTCF could increase its enzymatic activity however the specific mechanism by which and might be involved in the gene repression is poorly understood. Here, we show that CTCF and KDM4A form a protein complex, which is recruited into the first intron of . This is related to a decrease in H3K36me3/2 histone marks and is associated with its transcriptional downregulation. Depletion of or KDM4A by siRNA, triggered the reactivation of expression, suggesting that both proteins are involved in the negative regulation of this gene. Furthermore, the knockout of restored the expression and H3K36me3 and H3K36me2 histone marks. Such mechanism acts independently of promoter DNA methylation. Our findings support a novel mechanism of epigenetic repression at the gene body that does not involve promoter silencing.