Abstract
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.
Highlights
Repeat elements, including endogenous retroviral elements (ERVs), retrotransposable elements (RTEs) and telomeric repeats, represent more than half of the human genome
While the number of distal regions opening or closing in common myeloid progenitors (CMPs) or granulocyte-monocyte progenitors (GMPs) compared with long-term haematopoietic stem cells (LT-HSCs) were similar in the WT mice, substantially fewer distal regions were open in the Daxx-KO animals (Fig. 1b); most remained closed, suggesting Daxx-KO CMPs and GMPs became more restricted in their gene expression
We found DKO-specific chromatin changes: 15,587 distal regions that were open in WT and Daxx-KO Kit+Lineage (Lin)–Sca-1+ (KLS) cells became closed in DKO cells, while 3,922 distal sites that opened in DKO cells were closed in the other genotypes
Summary
End 0.5 kb H3K27ac (7,862) than those with reduced H3K9me[3] (1,147) compared with WT or Daxx-KO HSPCs. Fbp[1] silencing was restored in DKO cells, suggesting that Pu.[1] is required for its induction This is in accordance with three main regions bound by Pu.[1] at this locus (as reported in19), two of which coincide with haematopoietic enhancers[18]. The large block of H3K9me[3] over the Fbp[2] gene and its regulatory regions, which was previously linked to Fbp[2] upregulation in HSPCs43 following Setdb[1] loss, was further enriched in Daxx-KO cells but not DKO cells. H3K27me[3] was substantially reduced across the entire locus in the Daxx-KO and DKO cells, especially at the most proximal enhancer of Fbp[1], suggesting that this mark may cooperate with Pu.[1] loss for Fbp[1] silencing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
