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Comparative analysis of neutrophil and monocyte epigenomes

bioRxiv (Cold Spring Harbor Laboratory)2017

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D.E. Rico, Joost H.A. Martens, Kate Downes, Enrique Carrillo de Santa Pau, Véra Pancaldi, Alessandra Breschi, David Richardson, Simon Heath, Sadia Saeed, Mattia Frontini, Lu Chen, Stephen Watt, Fabian Müller, Laura Clarke, Hindrik H. D. Kerstens, Steven P. Wilder, Emilio Palumbo, Sarah Djebali, Emanuele Raineri, Angelika Merkel, Anna Esteve‐Codina, Marc Sultan, Alena van Bömmel, Marta Gut, Marie‐Laure Yaspo, Miriam Rubio, José M. Fernández, Anthony Attwood, Victor de la Torre, Romina Royo, Stamatina Fragkogianni, Josep Lluís Gelpí, David Torrents, Valentina Iotchkova, Colin Logie, Ali Aghajanirefah, Abhishek A. Singh, Eva M. Janssen‐Megens, Kim Berentsen, Wendy N. Erber, Augusto Rendon, Myrto Kostadima, Remco Loos, Martijn A. van der Ent, Anita Kaan, Nilofar Sharifi, Dirk S. Paul, Daniela C. Ifrim, Jessica Quintin, Michael I. Love, David G. Pisano, Frances Burden, Nicola Foad, Samantha Farrow, Daniel R. Zerbino, Ian Dunham, TacoW. Kuijpers, Hans Lehrach, Thomas Lengauer, Paul Bertone, Mihai G. Netea, Martin Vingron, Stephan Beck, Paul Flicek, Marta Gut, Willem H. Ouwehand, Christoph Bock, Nicole Soranzo, Rodericw Guigo, Alfonso Valencia, Hendrik G. Stunnenberg

Abstract

ABSTRACT Neutrophils and monocytes provide a first line of defense against infections as part of the innate immune system. Here we report the integrated analysis of transcriptomic and epigenetic landscapes for circulating monocytes and neutrophils with the aim to enable downstream interpretation and functional validation of key regulatory elements in health and disease. We collected RNA-seq data, ChIP-seq of six histone modifications and of DNA methylation by bisulfite sequencing at base pair resolution from up to 6 individuals per cell type. Chromatin segmentation analyses suggested that monocytes have a higher number of cell-specific enhancer regions (4-fold) compared to neutrophils. This highly plastic epigenome is likely indicative of the greater differentiation potential of monocytes into macrophages, dendritic cells and osteoclasts. In contrast, most of the neutrophil-specific features tend to be characterized by repressed chromatin, reflective of their status as terminally differentiated cells. Enhancers were the regions where most of differences in DNA methylation between cells were observed, with monocyte-specific enhancers being generally hypomethylated. Monocytes show a substantially higher gene expression levels than neutrophils, in line with epigenomic analysis revealing that gene more active elements in monocytes. Our analyses suggest that the overexpression of c-Myc in monocytes and its binding to monocyte-specific enhancers could be an important contributor to these differences. Altogether, our study provides a comprehensive epigenetic chart of chromatin states in primary human neutrophils and monocytes, thus providing a valuable resource for studying the regulation of the human innate immune system.

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Abstract

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