SummaryThe capacity of hematopoietic stem cells (HSC) to generate B lymphocytes declines with age, contributing to impaired immune function in the elderly. Here we show that the histone methyltransferase SUV39H1 plays an important role in human B lymphoid differentiation and that expression of SUV39H1 decreases with age in both human and mouse HSC, leading to a global reduction in H3K9 trimethylation and perturbed heterochromatin function. Further, we demonstrate that SUV39H1 is a target of microRNA miR-125b, a known regulator of HSC function, and that expression of miR-125b increases with age in human HSC. Overexpression of miR-125b and inhibition of SUV39H1 in young HSC induced loss of B cell potential. Conversely, both inhibition of miR-125 and enforced expression of SUV39H1 improved the capacity of HSC from elderly individuals to generate B cells. Our findings highlight the importance of heterochromatin regulation in HSC aging and B lymphopoiesis.
Transcription factor p45 NF‐E2 is highly expressed in the erythroid and megakaryocytic lineages. Although p45 recognizes regulatory regions of several erythroid genes, mice deficient for this protein display only mild dyserythropoiesis but have abnormal megakaryocytes and lack circulating platelets. A number of megakaryocytic marker genes have been extensively studied, but none of them is regulated by NF‐E2. To find target genes for p45 NF‐E2 in megakaryopoiesis, we used an in vivo immunoselection assay: genomic fragments bound to p45 NF‐E2 in the chromatin of a megakaryocytic cell line were immunoprecipitated with an anti‐p45 antiserum and cloned. One of these fragments belongs to the second intron of the thromboxane synthase gene (TXS). We demonstrate that the TXS gene, which is mainly expressed in megakaryocytes, is indeed directly regulated by p45 NF‐E2. First, its promoter contains a functional NF‐E2 binding site; second, the intronic NF‐E2 binding site is located within a chromatin‐dependent enhancer element; third, p45‐null murine megakaryocytes do not express detectable TXS mRNA, although TXS expression can be detected in other cells. These data, and the structure of the TXS promoter and enhancer, suggest that TXS belongs to a distinct subgroup of genes involved in platelet formation and function.
Within the bone marrow, the endosteal niche plays a crucial role in B-cell differentiation. Because spaceflight is associated with osteoporosis, we investigated whether changes in bone microstructure induced by a ground-based model of spaceflight, hind limb unloading (HU), could affect B lymphopoiesis. To this end, we analyzed both bone parameters and the frequency of early hematopoietic precursors and cells of the B lineage after 3, 6, 13, and 21 d of HU. We found that limb disuse leads to a decrease in both bone microstructure and the frequency of B-cell progenitors in the bone marrow. Although multipotent hematopoietic progenitors were not affected by HU, a decrease in B lymphopoiesis was observed as of the common lymphoid progenitor (CLP) stage with a major block at the progenitor B (pro-B) to precursor B (pre-B) cell transition (5-to 10-fold decrease). The modifications in B lymphopoiesis were similar to those observed in aged mice and, as with aging, decreased B-cell generation in HU mice was associated with reduced expression of B-cell transcription factors, early B-cell factor (EBF) and Pax5, and an alteration in STAT5-mediated IL-7 signaling. These findings demonstrate that mechanical unloading of hind limbs results in a decrease in early B-cell differentiation resembling age-related modifications in B lymphopoiesis.-Lescale, C., Schenten, V., Djeghloul, D., Bennabi, M., Gaignier, F., Vandamme, K., Strazielle, C., Kuzniak, I., Petite, H., Dosquet, C., Frippiat, J.-P., Goodhardt, M. Hind limb unloading, a model of spaceflight conditions, leads to decreased B lymphopoiesis similar to aging. FASEB J. 29, 455-463 (2015). www.fasebj.org Key Words: bone remodeling • B-cell differentiation • gravity • immunosenescence HUMAN BIOASTRONAUTIC PROGRAMS have grown during the last 50 yr. Medical and physiologic findings from these missions have demonstrated that spaceflight impacts almost all physiologic systems, including muscle atrophy, bone demineralization, cardiovascular and metabolic dysfunctions, impaired cognitive processes, and reduced immunologic competence. These adaptive responses can affect crew health and performance both in space and upon return to Earth. Indeed, 15 of the 29 Apollo astronauts contracted bacterial or viral infections either during the mission or within a week of returning (1-3). Prolonged exposure to microgravity induces osteopenia, with decreased bone formation and mineralization and increased bone resorption (4, 5), and there are presently no effective countermeasures to mitigate these problems. As a consequence, expanding our knowledge on the effects of longduration spaceflight on crew health and performance is clearly a prerequisite for long-term spaceflight.Immune-competent B and T lymphocytes are derived from hematopoietic stem cells (HSCs) that reside in the bone marrow in specialized niches made up of bone and vascular structures, including bone-forming osteoblasts and bone-resorbing osteoclasts (6). Interactions between HSC and bone marrow niches control the balance be...
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