Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex

Retinoic acid (RA) plays important roles in development, growth, and homeostasis through regulation of the nuclear receptors for RA (RARs). Herein, we identify Hypermethylated in Cancer 1 (Hic1) as an RA-inducible gene. HIC1 encodes a tumor suppressor, which is often silenced by promoter hypermethyl...

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Main Authors: Haider M. Hassan, Bart Kolendowski, Majdina Isovic, Kerstin Bose, Helen J. Dranse, Arthur V. Sampaio, T. Michael Underhill, Joseph Torchia
Format: Article
Language:English
Published: Elsevier 2017-05-01
Series:Cell Reports
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124717306149
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author Haider M. Hassan
Bart Kolendowski
Majdina Isovic
Kerstin Bose
Helen J. Dranse
Arthur V. Sampaio
T. Michael Underhill
Joseph Torchia
author_facet Haider M. Hassan
Bart Kolendowski
Majdina Isovic
Kerstin Bose
Helen J. Dranse
Arthur V. Sampaio
T. Michael Underhill
Joseph Torchia
author_sort Haider M. Hassan
collection DOAJ
description Retinoic acid (RA) plays important roles in development, growth, and homeostasis through regulation of the nuclear receptors for RA (RARs). Herein, we identify Hypermethylated in Cancer 1 (Hic1) as an RA-inducible gene. HIC1 encodes a tumor suppressor, which is often silenced by promoter hypermethylation in cancer. Treatment of cells with an RAR agonist causes a rapid recruitment of an RAR/RXR complex consisting of TDG, the lysine acetyltransferase CBP, and TET 1/2 to the Hic1 promoter. Complex binding coincides with a transient accumulation of 5fC/5caC and concomitant upregulation of Hic1 expression, both of which are TDG dependent. Furthermore, conditional deletion of Tdg in vivo is associated with Hic1 silencing and DNA hypermethylation of the Hic1 promoter. These findings suggest that the catalytic and scaffolding activities of TDG are essential for RA-dependent gene expression and provide important insights into the mechanisms underlying targeting of TET-TDG complexes.
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spelling doaj.art-6e03681522a548649af0972e5eb6f88e2022-12-22T02:24:09ZengElsevierCell Reports2211-12472017-05-011981685169710.1016/j.celrep.2017.05.007Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG ComplexHaider M. Hassan0Bart Kolendowski1Majdina Isovic2Kerstin Bose3Helen J. Dranse4Arthur V. Sampaio5T. Michael Underhill6Joseph Torchia7Department of Biochemistry, Western University, London, ON N6A 5C1, CanadaDepartment of Biochemistry, Western University, London, ON N6A 5C1, CanadaDepartment of Oncology, The London Regional Cancer Program and the Lawson Health Research Institute, London, ON N6A 4L6, CanadaDepartment of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDepartment of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDepartment of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDepartment of Cellular and Physiological Sciences and the Biomedical Research Centre, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDepartment of Biochemistry, Western University, London, ON N6A 5C1, CanadaRetinoic acid (RA) plays important roles in development, growth, and homeostasis through regulation of the nuclear receptors for RA (RARs). Herein, we identify Hypermethylated in Cancer 1 (Hic1) as an RA-inducible gene. HIC1 encodes a tumor suppressor, which is often silenced by promoter hypermethylation in cancer. Treatment of cells with an RAR agonist causes a rapid recruitment of an RAR/RXR complex consisting of TDG, the lysine acetyltransferase CBP, and TET 1/2 to the Hic1 promoter. Complex binding coincides with a transient accumulation of 5fC/5caC and concomitant upregulation of Hic1 expression, both of which are TDG dependent. Furthermore, conditional deletion of Tdg in vivo is associated with Hic1 silencing and DNA hypermethylation of the Hic1 promoter. These findings suggest that the catalytic and scaffolding activities of TDG are essential for RA-dependent gene expression and provide important insights into the mechanisms underlying targeting of TET-TDG complexes.http://www.sciencedirect.com/science/article/pii/S2211124717306149DNA methylationactive demethylationretinoic acidthymine DNA glycosylaseHypermethylated in Cancer 1
spellingShingle Haider M. Hassan
Bart Kolendowski
Majdina Isovic
Kerstin Bose
Helen J. Dranse
Arthur V. Sampaio
T. Michael Underhill
Joseph Torchia
Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex
Cell Reports
DNA methylation
active demethylation
retinoic acid
thymine DNA glycosylase
Hypermethylated in Cancer 1
title Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex
title_full Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex
title_fullStr Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex
title_full_unstemmed Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex
title_short Regulation of Active DNA Demethylation through RAR-Mediated Recruitment of a TET/TDG Complex
title_sort regulation of active dna demethylation through rar mediated recruitment of a tet tdg complex
topic DNA methylation
active demethylation
retinoic acid
thymine DNA glycosylase
Hypermethylated in Cancer 1
url http://www.sciencedirect.com/science/article/pii/S2211124717306149
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