Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation

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. 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.

Automated summary

The study reveals that the H3.3 chaperone Daxx acts as an epigenetic barrier to control haematopoietic progenitor plasticity and protect against PU.1-mediated inflammation by repressing endogenous retroviral and retrotransposable elements. Defective silencing of these elements has been linked to inflammageing, cancer, and autoimmune diseases, implicating a potential role for Daxx in protection from inflammatory diseases.