Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils

Grassi, L.; Pourfarzad, F.; Ullrich, S.; Merkel, A.; Were, F.; Carrillo de Santa Pau, E.; Yi, G.; Hiemstra, I. H.; Tool, A. T. J.; Mul, E.; Perner, J.; Janssen-Megens, E.; Berentsen, K.; Kerstens, H.; Habibi, E.; Gut, M.; Yaspo, M. L.; Linser, M.; Lowy, E.; Datta, A.; Clarke, L.; Flicek, P.; Vingron, M.; Roos, D.; van den Berg, T. K.; Heath, S.; Rico, D.; Frontini, M.; Kostadima, M.; Gut, I.; Valencia, A.; Ouwehand, W. H.; Stunnenberg, H. G.; Martens, J. H. A.; Kuijpers, T. W.

doi:10.1101/295014

Home/Archive/bioRxiv

bioRxiv · 10.1101/295014

Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils

View original source ↗Export metadata ↓

Abstract

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 and functional overview of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of epigenetic and transcriptome dynamics reveals an enforced regulation of differentiation, through cellular functions such as: release of proteases, respiratory burst, cell cycle regulation and apoptosis. We observe an early establishment of the cytotoxic capability, whilst the signaling components that activate 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 epigenetic landscape orchestrate the daily production of large number of neutrophils required for innate host defense and provide a comprehensive overview of the epigenomes of differentiating human neutrophils.\n\nKey pointsO_LIDynamic acetylation enforces human neutrophil progenitor differentiation.\nC_LI\n\nO_LINeutrophils cytotoxic capability is established early at the (pro)myelocyte stage.\nC_LI\n\nO_LICoordinated signaling component expression prevents unwanted toxic effects to the bone marrow niche.\nC_LI

Explore related subjects

immunology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Grassi, L., Pourfarzad, F., Ullrich, S., Merkel, A., Were, F., Carrillo de Santa Pau, E., Yi, G., Hiemstra, I. H., Tool, A. T. J., Mul, E., Perner, J., Janssen-Megens, E., Berentsen, K., Kerstens, H., Habibi, E., Gut, M., Yaspo, M. L., Linser, M., Lowy, E., Datta, A., Clarke, L., Flicek, P., Vingron, M., Roos, D., van den Berg, T. K., Heath, S., Rico, D., Frontini, M., Kostadima, M., Gut, I., Valencia, A., Ouwehand, W. H., Stunnenberg, H. G., Martens, J. H. A., Kuijpers, T. W.. 2018-04-05. Epigenomic and functional dynamics of human bone marrow myeloid differentiation to mature blood neutrophils. https://doi.org/10.1101/295014

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells in patients treated with CD19 chimeric antigen receptor (CAR) T cells (systemic lupus, n=6; idiopathic inflammatory myopathies, n=3; systemic sclerosis, n=3) or rituximab (n=15). CAR T cells, but not rituximab, depleted EBV+ B cells, resetting the repertoire toward a naive state: predominantly IgM+ with minimal somatic hypermutation. Post-rituximab B-cells remained class-switched, hypermutated, and activated. Monoclonal antibodies cloned from EBV+ B cells lost autoreactivity after CAR T cells but not rituximab. Sustained drug-free remission occurred in 8/12 CAR-treated but 0/15 rituximab-treated patients. EBV+ B cells were predominantly Latency III and resisted anti-CD20 and anti-CD19 antibodies, yet were killed by CAR T cells and T-cell engagers. CD19-CAR T-cell therapy resets the autoreactive EBV+ B-cell repertoire, which may underlie sustained drug-free remission.

immunology↗

bioRxiv2026

A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.

immunology↗

bioRxiv2026

Defining the Functional Consequence of the Human Ocular Microbiome

The ocular surface is one of the body's most environmentally exposed mucosal barriers, yet it is considered low biomass and harbors orders of magnitude fewer bacteria than microbe-rich sites like the gut. This has cast doubt on whether a functional core ocular microbiome exists at all. Having previously defined a protective gd T cell and IL-17 axis engaged by the murine commensal Corynebacterium mastitidis, we asked whether human-derived bacteria could do the same. Pairing sequencing and culturomics of healthy human conjunctiva from two geographically distinct cohorts, we define a stable core microbiome and identify Corynebacterium bovis as a consistent eye-resident commensal rather than a transient contaminant. In humans, C. bovis elicits a non-pathogenic response marked by IL-17 secretion by {gamma}{delta} T cells and circulating C. bovis-specific IgG, which suggests commensalism rather than pathology. Colonizing mice with human C. bovis strains from Pittsburgh or Miami reproduced this program and conferred protection against ocular infection with Staphylococcus aureus. Together, these findings identify C. bovis as a human-derived ocular commensal that can drive protective {gamma}{delta} T cell immunity, translating a mechanism previously defined only in mice into human relevance and a rational target against sight-threatening infection.

immunology↗