Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

Simone Ecker; Lu Chen; Vera Pancaldi; Frederik O Bagger; José María Fernández; Enrique Carrillo de Santa Pau; David Juan; Alice L Mann; Stephen Watt; Francesco Paolo Casale; Nikos Sidiropoulos; Nicolas Rapin; Angelika Merkel; BLUEPRINT Consortium; Hendrik G Stunnenberg; Oliver Stegle; Mattia Frontini; Kate Downes; Tomi Pastinen; Taco W Kuijpers; Daniel Rico; Alfonso Valencia; Stephan Beck; Nicole Soranzo; Dirk S Paul

doi:10.1186/s13059-017-1156-8

Genome-wide analysis of differential transcriptional and epigenetic variability across human immune cell types

Genome Biol. 2017 Jan 26;18(1):18. doi: 10.1186/s13059-017-1156-8.

Authors

Simone Ecker^{1

2}, Lu Chen^{3

4}, Vera Pancaldi⁵, Frederik O Bagger^{4

6

7}, José María Fernández⁵, Enrique Carrillo de Santa Pau⁵, David Juan⁵, Alice L Mann³, Stephen Watt³, Francesco Paolo Casale⁷, Nikos Sidiropoulos^{8

9

10}, Nicolas Rapin^{8

9

10}, Angelika Merkel¹¹; BLUEPRINT Consortium; Hendrik G Stunnenberg¹², Oliver Stegle⁷, Mattia Frontini^{4

6

13}, Kate Downes^{4

6}, Tomi Pastinen¹⁴, Taco W Kuijpers^{15

16}, Daniel Rico^{5

17}, Alfonso Valencia⁵, Stephan Beck¹⁸, Nicole Soranzo^{19

20}, Dirk S Paul^{21

22}

Collaborators

BLUEPRINT Consortium:
Cornelis A Albers, Vyacheslav Amstislavskiy, Sofie Ashford, Lorenzo Bomba, David Bujold, Frances Burden, Stephan Busche, Maxime Caron, Shu-Huang Chen, Warren A Cheung, Laura Clarke, Irina Colgiu, Avik Datta, Oliver Delaneau, Heather Elding, Samantha Farrow, Diego Garrido-Martín, Bing Ge, Roderic Guigo, Valentina Iotchkova, Kousik Kundu, Tony Kwan, John J Lambourne, Ernesto Lowy, Daniel Mead, Farzin Pourfarzad, Adriana Redensek, Karola Rehnstrom, Augusto Rendon, David Richardson, Thomas Risch, Sophia Rowlston, Xiaojian Shao, Marie-Michelle Simon, Marc Sultan, Klaudia Walter, Steven P Wilder, Ying Yan, Stylianos E Antonarakis, Guillaume Bourque, Emmanouil T Dermitzakis, Paul Flicek, Hans Lehrach, Joost H A Martens, Marie-Laure Yaspo, Willem H Ouwehand

Affiliations

¹ Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain. s.ecker@ucl.ac.uk.
² UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. s.ecker@ucl.ac.uk.
³ Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK.
⁴ Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK.
⁵ Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Melchor Fernández Almagro 3, 28029, Madrid, Spain.
⁶ National Health Service (NHS) Blood and Transplant, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
⁷ European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SD, UK.
⁸ The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
⁹ Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
¹⁰ The Bioinformatics Centre, Department of Biology, Faculty of Natural Sciences, University of Copenhagen, Ole Maaløes Vej 5, 2200, Copenhagen, Denmark.
¹¹ National Center for Genomic Analysis (CNAG), Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Carrer Baldiri i Reixac 4, 08028, Barcelona, Spain.
¹² Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, 6525GA, The Netherlands.
¹³ British Heart Foundation Centre of Excellence, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, CB2 0PT, UK.
¹⁴ Department of Human Genetics, McGill University, 740 Dr. Penfield, Montreal, H3A 0G1, Canada.
¹⁵ Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Plesmanlaan 125, Amsterdam, 1066CX, The Netherlands.
¹⁶ Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Location H7-230, Meibergdreef 9, Amsterdam, 1105AX, The Netherlands.
¹⁷ Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
¹⁸ UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK.
¹⁹ Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1HH, UK. ns6@sanger.ac.uk.
²⁰ Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Long Road, Cambridge, Hinxton, UK. ns6@sanger.ac.uk.
²¹ UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT, UK. dsp35@medschl.cam.ac.uk.
²² Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Wort's Causeway, Cambridge, CB1 8RN, UK. dsp35@medschl.cam.ac.uk.

Abstract

Background: A healthy immune system requires immune cells that adapt rapidly to environmental challenges. This phenotypic plasticity can be mediated by transcriptional and epigenetic variability.

Results: We apply a novel analytical approach to measure and compare transcriptional and epigenetic variability genome-wide across CD14⁺CD16^- monocytes, CD66b⁺CD16⁺ neutrophils, and CD4⁺CD45RA⁺ naïve T cells from the same 125 healthy individuals. We discover substantially increased variability in neutrophils compared to monocytes and T cells. In neutrophils, genes with hypervariable expression are found to be implicated in key immune pathways and are associated with cellular properties and environmental exposure. We also observe increased sex-specific gene expression differences in neutrophils. Neutrophil-specific DNA methylation hypervariable sites are enriched at dynamic chromatin regions and active enhancers.

Conclusions: Our data highlight the importance of transcriptional and epigenetic variability for the key role of neutrophils as the first responders to inflammatory stimuli. We provide a resource to enable further functional studies into the plasticity of immune cells, which can be accessed from: http://blueprint-dev.bioinfo.cnio.es/WP10/hypervariability .

Keywords: DNA methylation; Differential variability; Gene expression; Heterogeneity; Immune cells; Monocytes; Neutrophils; Phenotypic plasticity; T cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cluster Analysis
CpG Islands
DNA Methylation
Epigenesis, Genetic*
Female
Gene Expression Profiling
Gene Expression Regulation*
Gene Regulatory Networks
Genetic Variation
Genome-Wide Association Study*
Humans
Immune System / cytology*
Immune System / immunology
Immune System / metabolism*
Male
Neutrophils / metabolism
Organ Specificity / genetics
Sex Factors
Transcription, Genetic*

Abstract

Publication types

MeSH terms

Grants and funding