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
SN - 1949-2553
VL - 9
SP - 17028
EP - 17042
JO - Oncotarget
JF - Oncotarget
IS - 24
ER -
