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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. The work presented here was supported by the Landsteiner Foundation forBlood Transfusion Research (LSBR-1121 to T.W.K.) and by the Dutch CancerFoundation (KUN 2011-4 937 to J.H.A.M.). The work was funded by a grantfrom the European Commission 7th Framework Program (FP72007-2013,grant 282510, BLUEPRINT). M.F. ssupported sh Heart Foundation(BHF) Cambridge Centre of Excellence (RE/13/6/30180). Additional support wasrovided by the Wellcome Trust (WT108749/Z/15/Z to P.F.) and by the Eu-ropean Molecular Biology Laboratory (E.L., A.D.,L.C., P.F.). Research in theOuwehand laboratory is also supported by grants from Bristol-Myers Squibb,the British Heart Foundation, the Medical Research Council, the National Insti-tutefor Health Research (NIHR) (W.H.O. is senior investigator), and NHSBlood and Transplant (NHSB T). Sí

Immunodeficiency is one of the most important causes of mortality associated with Wolf-Hirschhorn syndrome (WHS), a severe rare disease originated by a deletion in chromosome 4p. The WHS candidate 1 (WHSC1) gene has been proposed as one of the main genes responsible for many of the alterations in WHS, but its mechanism of action is still unknown. Here, we present in vivo genetic evidence showing that Whsc1 plays an important role at several points of hematopoietic development. Particularly, our results demonstrate that both differentiation and function of Whsc1-deficient B cells are impaired at several key developmental stages due to profound molecular defects affecting B cell lineage specification, commitment, fitness, and proliferation, demonstrating a causal role for WHSC1 in the immunodeficiency of WHS patients., FEDER (Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III) (PI13/00160 and PI14/00025), Fundación Inocente Inocente, and the ARIMMORA EU/FP7 project and by donations from the Asociación Española del Síndrome de Wolf Hirschhorn (AESWH), the Fundación Síndrome de Wolf-Hirschhorn or 4p- (FSWH4p), FECYT Precipita, and Fundación Ramón Areces