Whole-genome Fingerprint of the DNA Methylome During Human B Cell Differentiation

Overview

Journal Nat Genet

Specialty Genetics

Date 2015 Jun 9

PMID 26053498

Citations 178

Authors

Marta Kulis

Angelika Merkel

Simon Heath

Ana C Queiros

Ronald P Schuyler

Giancarlo Castellano

Renee Beekman

Emanuele Raineri

Anna Esteve

Guillem Clot

Neria Verdaguer-Dot

Marti Duran-Ferrer

Nuria Russinol

Roser Vilarrasa-Blasi

Simone Ecker

Vera Pancaldi

Daniel Rico

Lidia Agueda

Julie Blanc

David Richardson

Laura Clarke

Avik Datta

Marien Pascual

Xabier Agirre

Felipe Prosper

Diego Alignani

Bruno Paiva

Gersende Caron

Thierry Fest

Marcus O Muench

Marina E Fomin

Seung-Tae Lee

Joseph L Wiemels

Alfonso Valencia

Marta Gut

Paul Flicek

Hendrik G Stunnenberg

Reiner Siebert

Ralf Kuppers

Ivo G Gut

Elias Campo

Jose I Martin-Subero

Affiliations

Soon will be listed here.

Abstract

We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.

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References

Hansen K, Timp W, Corrada Bravo H, Sabunciyan S, Langmead B, McDonald O . Increased methylation variation in epigenetic domains across cancer types. Nat Genet. 2011; 43(8):768-75. PMC: 3145050. DOI: 10.1038/ng.865. View

Habibi E, Brinkman A, Arand J, Kroeze L, Kerstens H, Matarese F . Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells. Cell Stem Cell. 2013; 13(3):360-9. DOI: 10.1016/j.stem.2013.06.002. View

Manz R, Thiel A, Radbruch A . Lifetime of plasma cells in the bone marrow. Nature. 1997; 388(6638):133-4. DOI: 10.1038/40540. View

Stadler M, Murr R, Burger L, Ivanek R, Lienert F, Scholer A . DNA-binding factors shape the mouse methylome at distal regulatory regions. Nature. 2011; 480(7378):490-5. DOI: 10.1038/nature10716. View

Martin-Subero J, Kreuz M, Bibikova M, Bentink S, Ammerpohl O, Wickham-Garcia E . New insights into the biology and origin of mature aggressive B-cell lymphomas by combined epigenomic, genomic, and transcriptional profiling. Blood. 2008; 113(11):2488-97. DOI: 10.1182/blood-2008-04-152900. View

Maksimovic J, Gordon L, Oshlack A . SWAN: Subset-quantile within array normalization for illumina infinium HumanMethylation450 BeadChips. Genome Biol. 2012; 13(6):R44. PMC: 3446316. DOI: 10.1186/gb-2012-13-6-r44. View

Hovestadt V, Jones D, Picelli S, Wang W, Kool M, Northcott P . Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature. 2014; 510(7506):537-41. DOI: 10.1038/nature13268. View

Matthias P, Rolink A . Transcriptional networks in developing and mature B cells. Nat Rev Immunol. 2005; 5(6):497-508. DOI: 10.1038/nri1633. View

Hon G, Rajagopal N, Shen Y, McCleary D, Yue F, Dang M . Epigenetic memory at embryonic enhancers identified in DNA methylation maps from adult mouse tissues. Nat Genet. 2013; 45(10):1198-206. PMC: 4095776. DOI: 10.1038/ng.2746. View

10.

Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C . The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2005; 439(7078):871-4. DOI: 10.1038/nature04431. View

11.

Lister R, Mukamel E, Nery J, Urich M, Puddifoot C, Johnson N . Global epigenomic reconfiguration during mammalian brain development. Science. 2013; 341(6146):1237905. PMC: 3785061. DOI: 10.1126/science.1237905. View

12.

Heyn H, Li N, Ferreira H, Moran S, Pisano D, Gomez A . Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A. 2012; 109(26):10522-7. PMC: 3387108. DOI: 10.1073/pnas.1120658109. View

13.

Xie W, Schultz M, Lister R, Hou Z, Rajagopal N, Ray P . Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell. 2013; 153(5):1134-48. PMC: 3786220. DOI: 10.1016/j.cell.2013.04.022. View

14.

Cedar H, Bergman Y . Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet. 2009; 10(5):295-304. DOI: 10.1038/nrg2540. View

15.

Berman B, Weisenberger D, Aman J, Hinoue T, Ramjan Z, Liu Y . Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat Genet. 2011; 44(1):40-6. PMC: 4309644. DOI: 10.1038/ng.969. View

16.

Lee S, Xiao Y, Muench M, Xiao J, Fomin M, Wiencke J . A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network. Nucleic Acids Res. 2012; 40(22):11339-51. PMC: 3526268. DOI: 10.1093/nar/gks957. View

17.

Arand J, Spieler D, Karius T, Branco M, Meilinger D, Meissner A . In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases. PLoS Genet. 2012; 8(6):e1002750. PMC: 3386304. DOI: 10.1371/journal.pgen.1002750. View

18.

Jaffe A, Irizarry R . Accounting for cellular heterogeneity is critical in epigenome-wide association studies. Genome Biol. 2014; 15(2):R31. PMC: 4053810. DOI: 10.1186/gb-2014-15-2-r31. View

19.

Tooze R . A replicative self-renewal model for long-lived plasma cells: questioning irreversible cell cycle exit. Front Immunol. 2014; 4:460. PMC: 3866514. DOI: 10.3389/fimmu.2013.00460. View

20.

Smith Z, Meissner A . DNA methylation: roles in mammalian development. Nat Rev Genet. 2013; 14(3):204-20. DOI: 10.1038/nrg3354. View