Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [ATAC-Seq]. Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [ATAC-Seq]

The lymphoid and myeloid lineages are in equilibrium during steady-state hematopoiesis. Tilting hematopoiesis towards innate immunity has been linked to inflammation and may predispose to myeloproliferative disease. Although epigenetic players have been implicated in the control of hematopoiesis and pathogenesis of blood neoplasms, the role of chromatin-based mechanisms in regulating the lymphoid/myeloid balance remains only partially understood. Here, we show that loss of the H3.3 chaperone Daxx causes myeloid skewing, neutrophilia and pyoderma gangrenosum-like lesions, a human skin disease of unknown etiology. Daxx deficiency leads to chromatin opening at intergenic regions, including TERRA target sites, deregulation of repeat elements and activation of anti-viral defense pathways. Finally, the other main H3.3 chaperone, Hira, is dispensable for normal hematopoiesis but supports expansion of Daxx-deficient neutrophils. These results define a role for Daxx in proper selection of lymphoid versus myeloid lineages, linked to control of repeat elements and anti-inflammatory responses. Overall design: Examination of gene expression profiles and chromatin accessibility in hematopoietic stem/progenitor cells comparing wild-type and Daxx knock-out cells.

稳态造血过程中，淋巴系与髓系谱系维持动态平衡。造血偏向固有免疫的状态与炎症反应相关，且可能增加骨髓增殖性疾病的患病风险。尽管表观调控因子已被证实参与造血调控及血液肿瘤的发病机制，但基于染色质的调控机制在维持淋巴/髓系平衡中的作用仍仅部分阐明。本研究发现，组蛋白H3.3伴侣蛋白Daxx的缺失会导致髓系偏倚、中性粒细胞增多症以及坏疽性脓皮病（pyoderma gangrenosum）样皮损——一种病因未明的人类皮肤疾病。Daxx缺陷会引发基因间区域（含端粒重复序列RNA（TERRA）靶点区域）的染色质开放、重复序列元件表达失调，并激活抗病毒防御通路。此外，另一主要组蛋白H3.3伴侣蛋白Hira在正常造血过程中并非必需，但可促进Daxx缺陷中性粒细胞的扩增。上述结果明确了Daxx在淋巴系与髓系谱系的正常定向选择中发挥的作用，该过程与重复序列元件的调控及抗炎反应相关。整体实验设计：对野生型与Daxx敲除造血干/祖细胞（hematopoietic stem/progenitor cells）的基因表达谱及染色质开放状态进行检测比对。