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
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1f6de9e1bc4c478a93769f666de093a8
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spelling	oai:doaj.org-article:1f6de9e1bc4c478a93769f666de093a82021-11-25T05:42:05ZThe Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function1553-734X1553-7358https://doaj.org/article/1f6de9e1bc4c478a93769f666de093a82021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601608/?tool=EBIhttps://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. Author summary In Eukaryotic cells, DNA epigenetic modifications play an important role in gene expression and regulation, and protein recognition. In this work we investigate the physical implications of cytosine 5-hydroxymethylation on DNA, its structural and flexibility differences with methylated and unmodified cytosine using molecular dynamics, biophysical experiments and NMR spectroscopy. In particular the effect of hydroxyl group on free energy of nucleosome and Methyl binding Protein (MBD) binding, comparing in silico and experimental data to shed light on the effect of the reduced flexibility and the direct protein-DNA recognition.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 (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. Author summary In Eukaryotic cells, DNA epigenetic modifications play an important role in gene expression and regulation, and protein recognition. In this work we investigate the physical implications of cytosine 5-hydroxymethylation on DNA, its structural and flexibility differences with methylated and unmodified cytosine using molecular dynamics, biophysical experiments and NMR spectroscopy. In particular the effect of hydroxyl group on free energy of nucleosome and Methyl binding Protein (MBD) binding, comparing in silico and experimental data to shed light on the effect of the reduced flexibility and the direct protein-DNA recognition.
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/1f6de9e1bc4c478a93769f666de093a8
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The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function

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