The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.
Authors
Castellazzi, Chiara L
Portella, Guillem
Orozco, Modesto
Publication Date
2021-11Journal Title
PLoS Comput Biol
ISSN
1553-734X
Publisher
Public Library of Science (PLoS)
Volume
17
Issue
11
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Battistini, F., Dans, P. D., Terrazas, M., Castellazzi, C. L., Portella, G., Labrador, M., Villegas, N., et al. (2021). The Impact of the HydroxyMethylCytosine epigenetic signature on DNA structure and function.. PLoS Comput Biol, 17 (11) https://doi.org/10.1371/journal.pcbi.1009547
Description
Funder: Government of Spain
Funder: Institució Catalana de Recerca i Estudis Avancats
Funder: Programa de Desarrollo de las Ciencias Basicas
Funder: Sistema Nacional de Investigadores, Agencia Nacional de Investigación e Innovación, Uruguay
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.
Keywords
Research Article, Biology and life sciences, Physical sciences
Sponsorship
spanish ministry of science (RTI2018-096704-B-100)
spanish ministry of science (BFU2017-89707-P)
Catalan goverment (SGR2017-134)
Instituto de Salud Carlos III (ISCIII PT 17/0009/0007)
H2020 European Research Council, BIOEXCEL2 (823830)
Identifiers
pcompbiol-d-21-01057
External DOI: https://doi.org/10.1371/journal.pcbi.1009547
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330900
Rights
Licence:
http://creativecommons.org/licenses/by/4.0/
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