TY - JOUR

T1 - CTCF-KDM4A complex correlates with histone modifications that negatively regulate CHD5 gene expression in cancer cell lines

AU - Guerra-Calderas, Lissania

AU - González-Barrios, Rodrigo

AU - Patiño, Carlos César

AU - Alcaraz, Nicolas

AU - Salgado-Albarrán, Marisol

AU - de León, David Cantú

AU - Hernández, Clementina Castro

AU - Sánchez-Pérez, Yesennia

AU - Maldonado-Martínez, Héctor Aquiles

AU - De la Rosa-Velazquez, Inti A.

AU - Vargas-Romero, Fernanda

AU - Herrera, Luis A.

AU - García-Carrancá, Alejandro

AU - Soto-Reyes, Ernesto

PY - 2018

Y1 - 2018

N2 - Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic modifications associated with gene silencing and RNA Polymerase II elongation, respectively. KDM4A is abnormally expressed in cancer, affecting the expression of multiple targets, such as the CHD5 gene. This enzyme localizes at the first intron of CHD5, and the dissociation of KDM4A increases gene expression. In vitro assays showed that KDM4A-mediated demethylation is enhanced in the presence of CTCF, suggesting that CTCF could increase its enzymatic activity in vivo, however the specific mechanism by which CTCF and KDM4A might be involved in the CHD5 gene repression is poorly understood. Here, we show that CTCF and KDM4A form a protein complex, which is recruited into the first intron of CHD5. This is related to a decrease in H3K36me3/2 histone marks and is associated with its transcriptional downregulation. Depletion of CTCF or KDM4A by siRNA, triggered the reactivation of CHD5 expression, suggesting that both proteins are involved in the negative regulation of this gene. Furthermore, the knockout of KDM4A restored the CHD5 expression and H3K36me3 and H3K36me2 histone marks. Such mechanism acts independently of CHD5 promoter DNA methylation. Our findings support a novel mechanism of epigenetic repression at the gene body that does not involve promoter silencing.

AB - Histone demethylase KDM4A is involved in H3K9me3 and H3K36me3 demethylation, which are epigenetic modifications associated with gene silencing and RNA Polymerase II elongation, respectively. KDM4A is abnormally expressed in cancer, affecting the expression of multiple targets, such as the CHD5 gene. This enzyme localizes at the first intron of CHD5, and the dissociation of KDM4A increases gene expression. In vitro assays showed that KDM4A-mediated demethylation is enhanced in the presence of CTCF, suggesting that CTCF could increase its enzymatic activity in vivo, however the specific mechanism by which CTCF and KDM4A might be involved in the CHD5 gene repression is poorly understood. Here, we show that CTCF and KDM4A form a protein complex, which is recruited into the first intron of CHD5. This is related to a decrease in H3K36me3/2 histone marks and is associated with its transcriptional downregulation. Depletion of CTCF or KDM4A by siRNA, triggered the reactivation of CHD5 expression, suggesting that both proteins are involved in the negative regulation of this gene. Furthermore, the knockout of KDM4A restored the CHD5 expression and H3K36me3 and H3K36me2 histone marks. Such mechanism acts independently of CHD5 promoter DNA methylation. Our findings support a novel mechanism of epigenetic repression at the gene body that does not involve promoter silencing.

KW - CHD5

KW - CTCF

KW - H3K36me

KW - Histone demethylation

KW - KDM4A

U2 - 10.18632/oncotarget.24798

DO - 10.18632/oncotarget.24798

M3 - Journal article

C2 - 29682202

AN - SCOPUS:85044780103

VL - 9

SP - 17028

EP - 17042

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 24

ER -