While the number of distal regions opening or closing in CMPs or GMPs compared with LT-HSCs were similar in the WT mice, substantially fewer distal regions were open in the Daxx-KO animals (Fig. Principal component analysis (PCA) showed separate clustering of WT and Daxx-KO samples (Extended Data Fig. Sorted LT-HSCs, common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) from wild-type (WT Daxx +/+ RosaCre ERT2+/–) and Daxx-KO ( Daxx F/F RosaCre ERT2+/–) mice were processed 3 weeks post tamoxifen treatment/induction (w.p.i.) for transposase-accessible chromatin sequencing (ATAC-seq Fig. To assess the impact of Daxx loss on the chromatin landscape of haematopoietic stem and progenitor cells (HSPCs), we crossed a conditional Daxx-knockout (KO) line with Rosa26CreERT2 mice (Extended Data Fig. However, their impact on tissue homeostasis, inflammation and oncogenesis remains only partially understood.Įxpression of Daxx, Atrx and the other H3.3 chaperone Hira 17 during haematopoiesis is enriched in long-term haematopoietic stem cells (LT-HSCs), megakaryocyte-erythrocyte progenitors and B cells (Extended Data Fig. Notably, loss-of-function mutations in DNA methyltransferases, DAXX and ATRX are found in human cancer, including myeloid malignancies 12, 13, 14, 15, 16. Loss of ERV/RTE silencing may activate their enhancer function in embryonic stem cells 11. In embryonic stem cells, DNA methylation and incorporation of the histone 3.3 (H3.3) variant via the Death domain-associated protein (Daxx)–Alpha-thalassaemia X-linked mental retardation (Atrx) complex restricts accessibility to selected RTEs, such as intracisternal particles (IAPs) 9, 10. Given the pleiotropic roles of ERVs/RTEs and their potentially detrimental effects on cell and tissue homeostasis, several mechanisms are in place to regulate their accessibility and expression. Aberrant opening and/or expression of ERVs/RTEs has been linked to inflammageing, cancer and autoimmunity 4, 5, 6, 7, 8. ERVs and RTEs (ERVs/RTEs) have emerged as important regulators of key DNA- and RNA-based cellular functions, such as assembly of transcriptional networks, splicing and mutagenesis 1, 2, 3. Repeat elements, including endogenous retroviral elements (ERVs), retrotransposable elements (RTEs) and telomeric repeats, represent more than half of the human genome. 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. 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. This causes neutrophilia and inflammation, predisposing mice to develop an autoinflammatory skin 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. 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. However, the underlying mechanisms are only partially understood. Nature Cell Biology volume 23, pages 1224–1239 ( 2021) Cite this articleĭefective silencing of retrotransposable elements has been linked to inflammageing, cancer and autoimmune diseases. 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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