Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a

Rachel Deplus; Loïc Blanchon; Arumugam Rajavelu; Abdelhalim Boukaba; Matthieu Defrance; Judith Luciani; Françoise Rothé; Sarah Dedeurwaerder; Hélène Denis; Arie B. Brinkman; Femke Simmer; Fabian Müller; Benjamin Bertin; Maria Berdasco; Pascale Putmans; Emilie Calonne; David W. Litchfield; Yvan De Launoit; Tomasz P. Jurkowski; Hendrik G. Stunnenberg; Christoph Bock; Christos Sotiriou; Mario F. Fraga; Manel Esteller; Albert Jeltsch; François Fuks

doi:10.1016/j.celrep.2014.06.048

Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a

Rachel Deplus, Loïc Blanchon, Arumugam Rajavelu, Abdelhalim Boukaba, Matthieu Defrance, Judith Luciani, Françoise Rothé, Sarah Dedeurwaerder, Hélène Denis, Arie B. Brinkman, Femke Simmer, Fabian Müller, Benjamin Bertin, Maria Berdasco, Pascale Putmans, Emilie Calonne, David W. Litchfield, Yvan De Launoit, Tomasz P. Jurkowski, Hendrik G. StunnenbergChristoph Bock, Christos Sotiriou, Mario F. Fraga, Manel Esteller, Albert Jeltsch, François Fuks

Research output: Contribution to journal › Article › peer-review

67 Citations (Scopus)

Abstract

DNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns.

Original language	English
Pages (from-to)	743-753
Number of pages	11
Journal	Cell Reports
Volume	8
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.06.048
Publication status	Published - 7 Aug 2014
Externally published	Yes

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10.1016/j.celrep.2014.06.048

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Deplus, R., Blanchon, L., Rajavelu, A., Boukaba, A., Defrance, M., Luciani, J., Rothé, F., Dedeurwaerder, S., Denis, H., Brinkman, A. B., Simmer, F., Müller, F., Bertin, B., Berdasco, M., Putmans, P., Calonne, E., Litchfield, D. W., De Launoit, Y., Jurkowski, T. P., ... Fuks, F. (2014). Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a. Cell Reports, 8(3), 743-753. https://doi.org/10.1016/j.celrep.2014.06.048

@article{cb57a8f71c724bcbbcd0d78c5373ab24,

title = "Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a",

abstract = "DNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns.",

author = "Rachel Deplus and Lo{\"i}c Blanchon and Arumugam Rajavelu and Abdelhalim Boukaba and Matthieu Defrance and Judith Luciani and Fran{\c c}oise Roth{\'e} and Sarah Dedeurwaerder and H{\'e}l{\`e}ne Denis and Brinkman, {Arie B.} and Femke Simmer and Fabian M{\"u}ller and Benjamin Bertin and Maria Berdasco and Pascale Putmans and Emilie Calonne and Litchfield, {David W.} and {De Launoit}, Yvan and Jurkowski, {Tomasz P.} and Stunnenberg, {Hendrik G.} and Christoph Bock and Christos Sotiriou and Fraga, {Mario F.} and Manel Esteller and Albert Jeltsch and Fran{\c c}ois Fuks",

note = "Publisher Copyright: {\textcopyright} 2014 The Authors.",

year = "2014",

month = aug,

day = "7",

doi = "10.1016/j.celrep.2014.06.048",

language = "English",

volume = "8",

pages = "743--753",

journal = "Cell Reports",

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Deplus, R, Blanchon, L, Rajavelu, A, Boukaba, A, Defrance, M, Luciani, J, Rothé, F, Dedeurwaerder, S, Denis, H, Brinkman, AB, Simmer, F, Müller, F, Bertin, B, Berdasco, M, Putmans, P, Calonne, E, Litchfield, DW, De Launoit, Y, Jurkowski, TP, Stunnenberg, HG, Bock, C, Sotiriou, C, Fraga, MF, Esteller, M, Jeltsch, A & Fuks, F 2014, 'Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a', Cell Reports, vol. 8, no. 3, pp. 743-753. https://doi.org/10.1016/j.celrep.2014.06.048

TY - JOUR

T1 - Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a

AU - Deplus, Rachel

AU - Blanchon, Loïc

AU - Rajavelu, Arumugam

AU - Boukaba, Abdelhalim

AU - Defrance, Matthieu

AU - Luciani, Judith

AU - Rothé, Françoise

AU - Dedeurwaerder, Sarah

AU - Denis, Hélène

AU - Brinkman, Arie B.

AU - Simmer, Femke

AU - Müller, Fabian

AU - Bertin, Benjamin

AU - Berdasco, Maria

AU - Putmans, Pascale

AU - Calonne, Emilie

AU - Litchfield, David W.

AU - De Launoit, Yvan

AU - Jurkowski, Tomasz P.

AU - Stunnenberg, Hendrik G.

AU - Bock, Christoph

AU - Sotiriou, Christos

AU - Fraga, Mario F.

AU - Esteller, Manel

AU - Jeltsch, Albert

AU - Fuks, François

PY - 2014/8/7

Y1 - 2014/8/7

N2 - DNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns.

AB - DNA methylation is a central epigenetic modification that is established by de novo DNA methyltransferases. The mechanisms underlying the generation of genomic methylation patterns are still poorly understood. Using mass spectrometry and a phosphospecific Dnmt3a antibody, we demonstrate that CK2 phosphorylates endogenous Dnmt3a at two key residues located near its PWWP domain, thereby downregulating the ability of Dnmt3a to methylate DNA. Genome-wide DNA methylation analysis shows that CK2 primarily modulates CpG methylation of several repeats, most notably of Alu SINEs. This modulation can be directly attributed to CK2-mediated phosphorylation of Dnmt3a. We also find that CK2-mediated phosphorylation is required for localization of Dnmt3a to heterochromatin. By revealing phosphorylation as a mode of regulation of de novo DNA methyltransferase function and by uncovering a mechanism for the regulation of methylation at repetitive elements, our results shed light on the origin of DNA methylation patterns.

UR - http://www.scopus.com/inward/record.url?scp=84919776252&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2014.06.048

DO - 10.1016/j.celrep.2014.06.048

M3 - Article

C2 - 25066127

AN - SCOPUS:84919776252

SN - 2211-1247

VL - 8

SP - 743

EP - 753

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

Regulation of DNA methylation patterns by CK2-mediated phosphorylation of Dnmt3a

Abstract

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