The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.

We present a comprehensive, experimental and theoretical study of the impact of 5-hydroxymethylation of DNA cytosine. Using molecular dynamics, biophysical experiments and NMR spectroscopy, we found that Ten-Eleven translocation (TET) dioxygenases generate an epigenetic variant with structural and p...

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Autores principales: Federica Battistini, Pablo D Dans, Montserrat Terrazas, Chiara L Castellazzi, Guillem Portella, Mireia Labrador, Núria Villegas, Isabelle Brun-Heath, Carlos González, Modesto Orozco
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Acceso en línea:https://doaj.org/article/ca080e6057bb4d7ba1268ebcdd0dc93a
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spelling oai:doaj.org-article:ca080e6057bb4d7ba1268ebcdd0dc93a2021-12-02T19:57:59ZThe Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.1553-734X1553-735810.1371/journal.pcbi.1009547https://doaj.org/article/ca080e6057bb4d7ba1268ebcdd0dc93a2021-11-01T00:00:00Zhttps://doi.org/10.1371/journal.pcbi.1009547https://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358We present a comprehensive, experimental and theoretical study of the impact of 5-hydroxymethylation of DNA cytosine. Using molecular dynamics, biophysical experiments and NMR spectroscopy, we found that Ten-Eleven translocation (TET) dioxygenases generate an epigenetic variant with structural and physical properties similar to those of 5-methylcytosine. Experiments and simulations demonstrate that 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) generally lead to stiffer DNA than normal cytosine, with poorer circularization efficiencies and lower ability to form nucleosomes. In particular, we can rule out the hypothesis that hydroxymethylation reverts to unmodified cytosine physical properties, as hmC is even more rigid than mC. Thus, we do not expect dramatic changes in the chromatin structure induced by differences in physical properties between d(mCpG) and d(hmCpG). Conversely, our simulations suggest that methylated-DNA binding domains (MBDs), associated with repression activities, are sensitive to the substitution d(mCpG) ➔ d(hmCpG), while MBD3 which has a dual activation/repression activity is not sensitive to the d(mCpG) d(hmCpG) change. Overall, while gene activity changes due to cytosine methylation are the result of the combination of stiffness-related chromatin reorganization and MBD binding, those associated to 5-hydroxylation of methylcytosine could be explained by a change in the balance of repression/activation pathways related to differential MBD binding.Federica BattistiniPablo D DansMontserrat TerrazasChiara L CastellazziGuillem PortellaMireia LabradorNúria VillegasIsabelle Brun-HeathCarlos GonzálezModesto OrozcoPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 17, Iss 11, p e1009547 (2021)
institution DOAJ
collection DOAJ
language EN
topic Biology (General)
QH301-705.5
spellingShingle Biology (General)
QH301-705.5
Federica Battistini
Pablo D Dans
Montserrat Terrazas
Chiara L Castellazzi
Guillem Portella
Mireia Labrador
Núria Villegas
Isabelle Brun-Heath
Carlos González
Modesto Orozco
The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
description We present a comprehensive, experimental and theoretical study of the impact of 5-hydroxymethylation of DNA cytosine. Using molecular dynamics, biophysical experiments and NMR spectroscopy, we found that Ten-Eleven translocation (TET) dioxygenases generate an epigenetic variant with structural and physical properties similar to those of 5-methylcytosine. Experiments and simulations demonstrate that 5-methylcytosine (mC) and 5-hydroxymethylcytosine (hmC) generally lead to stiffer DNA than normal cytosine, with poorer circularization efficiencies and lower ability to form nucleosomes. In particular, we can rule out the hypothesis that hydroxymethylation reverts to unmodified cytosine physical properties, as hmC is even more rigid than mC. Thus, we do not expect dramatic changes in the chromatin structure induced by differences in physical properties between d(mCpG) and d(hmCpG). Conversely, our simulations suggest that methylated-DNA binding domains (MBDs), associated with repression activities, are sensitive to the substitution d(mCpG) ➔ d(hmCpG), while MBD3 which has a dual activation/repression activity is not sensitive to the d(mCpG) d(hmCpG) change. Overall, while gene activity changes due to cytosine methylation are the result of the combination of stiffness-related chromatin reorganization and MBD binding, those associated to 5-hydroxylation of methylcytosine could be explained by a change in the balance of repression/activation pathways related to differential MBD binding.
format article
author Federica Battistini
Pablo D Dans
Montserrat Terrazas
Chiara L Castellazzi
Guillem Portella
Mireia Labrador
Núria Villegas
Isabelle Brun-Heath
Carlos González
Modesto Orozco
author_facet Federica Battistini
Pablo D Dans
Montserrat Terrazas
Chiara L Castellazzi
Guillem Portella
Mireia Labrador
Núria Villegas
Isabelle Brun-Heath
Carlos González
Modesto Orozco
author_sort Federica Battistini
title The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
title_short The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
title_full The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
title_fullStr The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
title_full_unstemmed The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
title_sort impact of the hydroxymethylcytosine epigenetic signature on dna structure and function.
publisher Public Library of Science (PLoS)
publishDate 2021
url https://doaj.org/article/ca080e6057bb4d7ba1268ebcdd0dc93a
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