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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Battistini, Federica  ORCID logo  https://orcid.org/0000-0002-7544-0938
Terrazas, Montserrat  ORCID logo  https://orcid.org/0000-0001-8614-5777
Castellazzi, Chiara L 
Portella, Guillem 

Abstract

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.

Description

Funder: Programa de Desarrollo de las Ciencias Basicas


Funder: Institució Catalana de Recerca i Estudis Avancats


Funder: Sistema Nacional de Investigadores, Agencia Nacional de Investigación e Innovación, Uruguay


Funder: Government of Spain

Keywords

5-Methylcytosine, Binding Sites, Biophysical Phenomena, Computational Biology, DNA, DNA Methylation, Epigenesis, Genetic, Humans, Magnetic Resonance Spectroscopy, Models, Biological, Molecular Dynamics Simulation, Nucleic Acid Conformation

Journal Title

PLoS Comput Biol

Conference Name

Journal ISSN

1553-734X
1553-7358

Volume Title

17

Publisher

Public Library of Science (PLoS)
Sponsorship
spanish ministry of science (RTI2018-096704-B-100, BFU2017-89707-P)
Catalan goverment (SGR2017-134)
Instituto de Salud Carlos III (ISCIII PT 17/0009/0007)
H2020 European Research Council, BIOEXCEL2 (823830)
European Research Council (823830)