Dynamics of Transcription Regulation in Human Bone Marrow Myeloid Differentiation to Mature Blood Neutrophils

Luigi Grassi, Farzin Pourfarzad, Sebastian Ullrich, Angelika Merkel, Felipe Were, Enrique Carrillo-de-Santa-Pau, Guoqiang Yi, Ida H. Hiemstra, Anton T.J. Tool, Erik Mul, Juliane Perner, Eva Janssen-Megens, Kim Berentsen, Hinri Kerstens, Ehsan Habibi, Marta Gut, Marie Laure Yaspo, Matthias Linser, Ernesto Lowy, Avik Datta, Laura Clarke, Paul Flicek, Martin Vingron, Dirk Roos, Timo K. van den Berg, Simon Heath, Daniel Rico, Mattia Frontini, Myrto Kostadima, Ivo Gut, Alfonso Valencia, Willem H. Ouwehand, Hendrik G. Stunnenberg, Joost H.A. Martens, Taco W. Kuijpers

Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils.