Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.
Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.
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DOI：
10.1038/s41556-021-00774-y
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发表时间：
2021-12
影响因子：
21.3
通讯作者：
Salomoni P
中科院分区：
文献类型：
--
作者：
Gerber JP;Russ J;Chandrasekar V;Offermann N;Lee HM;Spear S;Guzzi N;Maida S;Pattabiraman S;Zhang R;Kayvanjoo AH;Datta P;Kasturiarachchi J;Sposito T;Izotova N;Händler K;Adams PD;Marafioti T;Enver T;Wenzel J;Beyer M;Mass E;Bellodi C;Schultze JL;Capasso M;Nimmo R;Salomoni P
逆转录转座因子的缺陷性沉默与炎症、癌症和自身免疫性疾病有关。然而，基本的机制只被部分理解。在这里，我们牵连组蛋白H3.3分子伴侣Daxx，一个逆转录转座因子阻遏物失活的髓性白血病和其他肿瘤，在保护炎症性疾病。Daxx的丢失改变了造血祖细胞的染色质景观、H3.3分布和组蛋白标记，导致以B细胞分化为代价参与骨髓生成的Pu.1依赖性转录程序。这会导致嗜中性和炎症，使小鼠容易患上自身炎症性皮肤病。虽然这些分子和表型扰动在缺乏Pu.1和Daxx的动物中部分逆转，但这些小鼠中的造血祖细胞显示出独特的染色质和转录组改变，表明这两种途径之间存在相互作用。总的来说，我们的研究结果牵连逆转录转座因子沉默造血，并建议之间的H3.3加载机器和先锋转录因子Pu.1的串扰。Gerber，Russ等人表明，抑制内源性逆转录病毒和逆转录转座因子的H3.3分子伴侣Daxx充当表观遗传屏障，以控制造血祖细胞可塑性并防止PU.1介导的炎症。
Defective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. However, the underlying mechanisms are only partially understood. Here we implicate the histone H3.3 chaperone Daxx, a retrotransposable element repressor inactivated in myeloid leukaemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx alters the chromatin landscape, H3.3 distribution and histone marks of haematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional programme for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin disease. While these molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx, haematopoietic progenitors in these mice show unique chromatin and transcriptome alterations, suggesting an interaction between these two pathways. Overall, our findings implicate retrotransposable element silencing in haematopoiesis and suggest a cross-talk between the H3.3 loading machinery and the pioneer transcription factor Pu.1. Gerber, Russ et al. show that the H3.3 chaperone Daxx, which represses endogenous retroviral and retrotransposable elements, acts as an epigenetic barrier to control haematopoietic progenitor plasticity and protect against PU.1-mediated inflammation.
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