Histone H3.3 ensures cell proliferation and genomic stability during myeloid cell development

Variant histone H3.3 is thought to be critical for the survival of many cells, since it is deposited in expressed genes. For example, H3.3 deletion leads to embryonic lethality in mice. However, the requirement of H3.3 in the later stages of development has remained unclear. The aim of this work was to elucidate the role of H3.3 for the development of myeloid lineage, which is important for innate immunity. We conditionally knocked out (cKO) the H3.3 genes in myeloid progenitor cells differentiating into bone marrow-derived macrophages (BMDMs). Progenitor cells lacking H3.3 were defective in replication, suffered from extensive DNA damage, and underwent apoptosis. Surviving H3.3cKO cells expressed many interferon-stimulated genes throughout differentiation. Further, H3.3cKO BMDMs possessed chromatin accessible sites, histone posttranslational modifications consistent with the gene expression profiles, and retained general nucleosomal structure genome-wide. In summary, H3.3 is required for the proliferation of myeloid progenitor cells but is not totally indispensable for the differentiation of BMDMs.