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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE119306 | GEO | 2021/08/31

REPOSITORIES: GEO

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Project description:Objective: Daxx is a protein with multiple functions and is essential for embryonic development. Daxx knockout embryos fail to develop properly and exhibit lethal phenotype around E6.5. One of the important functions is as a histone chaperone for the histone H3 variant, H3.3. Daxx interacts with Atrx to form a protein complex that deposits H3.3 into heterochromatic regions of the genome, including centromeres, telomeres and repeat loci. Here, we investigated how histone chaperone function of Daxx contributes to the embryonic development. Methods: We developed two Daxx mutant alleles in the mouse germline which abolish the interactions between Daxx and Atrx (DaxxY130A), Daxx and H3.3 (DaxxS226A). We set up mating between either heterozygous DaxxY130A or heterozygous DaxxS226A individually and looked for the viability of homozygous mutants at different development stages. We also performed bulk RNA-seq on tissues from the two mutant embryos and analyzed the changes in gene expression and transposable elements (TE). Results: We found that the interaction between Daxx and Atrx is dispensable for viability in both the pre- and post-natal setting as homozygous Daxx-Y130A mutants are both viable and fertile. The loss of the Atrx interaction, however, does cause dysregulated expression of both endogenous retroviruses and nearby protein coding genes. On the contrary, the interaction between Daxx and H3.3 is not required for embryonic development but is essential for postnatal viability. Transcriptome analysis of embryonic tissues demonstrates that this interaction is important for silencing endogenous retroviruses and for maintaining proper hematopoiesis. Conclusions: The histone chaperone function of Daxx is dispensable for embryonic development but important for hematopoiesis, which is independent of the interaction with Atrx. Moreover, both the interactions with Atrx and with H3.3 is important for regulation of ERV expression. Overall, these results clearly demonstrate that Daxx and H3.3 have both Atrx-dependent and independent functions, advancing our understanding of this epigenetic regulatory complex.

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

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