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Impaired DNA demethylation of C/EBP sites causes premature aging
Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049513/ https://www.ncbi.nlm.nih.gov/pubmed/29884649 http://dx.doi.org/10.1101/gad.311969.118 |
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author | Schäfer, Andrea Mekker, Bernadette Mallick, Medhavi Vastolo, Viviana Karaulanov, Emil Sebastian, Dominik von der Lippen, Carina Epe, Bernd Downes, Damien J. Scholz, Carola Niehrs, Christof |
author_facet | Schäfer, Andrea Mekker, Bernadette Mallick, Medhavi Vastolo, Viviana Karaulanov, Emil Sebastian, Dominik von der Lippen, Carina Epe, Bernd Downes, Damien J. Scholz, Carola Niehrs, Christof |
author_sort | Schäfer, Andrea |
collection | PubMed |
description | Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that Gadd45a/Ing1 double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of Cebp (CCAAT/enhancer-binding protein) mutants. Correspondingly, GADD45α occupies C/EBPβ/δ-dependent superenhancers and, cooperatively with ING1, promotes local DNA demethylation via long-range chromatin loops to permit C/EBPβ recruitment. The results indicate that enhancer methylation can affect aging and imply that C/EBP proteins play an unexpected role in this process. Our study suggests a causal nexus between DNA demethylation, metabolism, and organismal aging. |
format | Online Article Text |
id | pubmed-6049513 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-60495132018-12-01 Impaired DNA demethylation of C/EBP sites causes premature aging Schäfer, Andrea Mekker, Bernadette Mallick, Medhavi Vastolo, Viviana Karaulanov, Emil Sebastian, Dominik von der Lippen, Carina Epe, Bernd Downes, Damien J. Scholz, Carola Niehrs, Christof Genes Dev Research Paper Changes in DNA methylation are among the best-documented epigenetic alterations accompanying organismal aging. However, whether and how altered DNA methylation is causally involved in aging have remained elusive. GADD45α (growth arrest and DNA damage protein 45A) and ING1 (inhibitor of growth family member 1) are adapter proteins for site-specific demethylation by TET (ten-eleven translocation) methylcytosine dioxygenases. Here we show that Gadd45a/Ing1 double-knockout mice display segmental progeria and phenocopy impaired energy homeostasis and lipodystrophy characteristic of Cebp (CCAAT/enhancer-binding protein) mutants. Correspondingly, GADD45α occupies C/EBPβ/δ-dependent superenhancers and, cooperatively with ING1, promotes local DNA demethylation via long-range chromatin loops to permit C/EBPβ recruitment. The results indicate that enhancer methylation can affect aging and imply that C/EBP proteins play an unexpected role in this process. Our study suggests a causal nexus between DNA demethylation, metabolism, and organismal aging. Cold Spring Harbor Laboratory Press 2018-06-01 /pmc/articles/PMC6049513/ /pubmed/29884649 http://dx.doi.org/10.1101/gad.311969.118 Text en © 2018 Schäfer et al.; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Research Paper Schäfer, Andrea Mekker, Bernadette Mallick, Medhavi Vastolo, Viviana Karaulanov, Emil Sebastian, Dominik von der Lippen, Carina Epe, Bernd Downes, Damien J. Scholz, Carola Niehrs, Christof Impaired DNA demethylation of C/EBP sites causes premature aging |
title | Impaired DNA demethylation of C/EBP sites causes premature aging |
title_full | Impaired DNA demethylation of C/EBP sites causes premature aging |
title_fullStr | Impaired DNA demethylation of C/EBP sites causes premature aging |
title_full_unstemmed | Impaired DNA demethylation of C/EBP sites causes premature aging |
title_short | Impaired DNA demethylation of C/EBP sites causes premature aging |
title_sort | impaired dna demethylation of c/ebp sites causes premature aging |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049513/ https://www.ncbi.nlm.nih.gov/pubmed/29884649 http://dx.doi.org/10.1101/gad.311969.118 |
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