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

Lissania Guerra-Calderas; Rodrigo González-Barrios; Carlos César Patiño; Nicolas Alcaraz; Marisol Salgado-Albarrán; David Cantú de León; Clementina Castro Hernández; Yesennia Sánchez-Pérez; Héctor Aquiles Maldonado-Martínez; Inti A. De la Rosa-Velazquez; Fernanda Vargas-Romero; Luis A. Herrera; Alejandro García-Carrancá; Ernesto Soto-Reyes

doi:10.18632/oncotarget.24798

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

Lissania Guerra-Calderas, Rodrigo González-Barrios, Carlos César Patiño, Nicolas Alcaraz, Marisol Salgado-Albarrán, David Cantú de León, Clementina Castro Hernández, Yesennia Sánchez-Pérez, Héctor Aquiles Maldonado-Martínez, Inti A. De la Rosa-Velazquez, Fernanda Vargas-Romero, Luis A. Herrera, Alejandro García-Carrancá, Ernesto Soto-Reyes^*

^*Corresponding author for this work

Computational and RNA Biology

3 Citations (Scopus)

Abstract

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.

Original language	English
Journal	OncoTarget
Volume	9
Issue number	24
Pages (from-to)	17028-17042
Number of pages	15
ISSN	1949-2553
DOIs	https://doi.org/10.18632/oncotarget.24798
Publication status	Published - 2018

Keywords

CHD5
CTCF
H3K36me
Histone demethylation
KDM4A

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.24798Licence: CC BY

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Guerra-Calderas, L., González-Barrios, R., Patiño, C. C., Alcaraz, N., Salgado-Albarrán, M., de León, D. C., Hernández, C. C., Sánchez-Pérez, Y., Maldonado-Martínez, H. A., De la Rosa-Velazquez, I. A., Vargas-Romero, F., Herrera, L. A., García-Carrancá, A., & Soto-Reyes, E. (2018). CTCF-KDM4A complex correlates with histone modifications that negatively regulate CHD5 gene expression in cancer cell lines. OncoTarget, 9(24), 17028-17042. https://doi.org/10.18632/oncotarget.24798

Guerra-Calderas, L, González-Barrios, R, Patiño, CC, Alcaraz, N, Salgado-Albarrán, M, de León, DC, Hernández, CC, Sánchez-Pérez, Y, Maldonado-Martínez, HA, De la Rosa-Velazquez, IA, Vargas-Romero, F, Herrera, LA, García-Carrancá, A & Soto-Reyes, E 2018, 'CTCF-KDM4A complex correlates with histone modifications that negatively regulate CHD5 gene expression in cancer cell lines', OncoTarget, vol. 9, no. 24, pp. 17028-17042. https://doi.org/10.18632/oncotarget.24798

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title = "CTCF-KDM4A complex correlates with histone modifications that negatively regulate CHD5 gene expression in cancer cell lines",

abstract = "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.",

keywords = "CHD5, CTCF, H3K36me, Histone demethylation, KDM4A",

author = "Lissania Guerra-Calderas and Rodrigo Gonz{\'a}lez-Barrios and Pati{\~n}o, {Carlos C{\'e}sar} and Nicolas Alcaraz and Marisol Salgado-Albarr{\'a}n and {de Le{\'o}n}, {David Cant{\'u}} and Hern{\'a}ndez, {Clementina Castro} and Yesennia S{\'a}nchez-P{\'e}rez and Maldonado-Mart{\'i}nez, {H{\'e}ctor Aquiles} and {De la Rosa-Velazquez}, {Inti A.} and Fernanda Vargas-Romero and Herrera, {Luis A.} and Alejandro Garc{\'i}a-Carranc{\'a} and Ernesto Soto-Reyes",

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doi = "10.18632/oncotarget.24798",

language = "English",

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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 -

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

Abstract

Keywords

UN SDGs

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