Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.
Julia P GerberJenny RussVijay ChandrasekarNina OffermannHang-Mao LeeSarah SpearNicola GuzziSimona MaidaSundararaghavan PattabiramanRuoyu ZhangAmir H KayvanjooPreeta DattaJagath KasturiarachchiTeresa SpositoNatalia IzotovaKristian HändlerPeter D AdamsTeresa MarafiotiTariq EnverJörg WenzelMarc BeyerElvira MassCristian BellodiJoachim L SchultzeMelania CapassoRachael NimmoPaolo SalomoniPublished in: Nature cell biology (2021)
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.
Keyphrases
- transcription factor
- gene expression
- oxidative stress
- genome wide
- dna damage
- single cell
- dna binding
- dna methylation
- high fat diet induced
- heat shock protein
- papillary thyroid
- heat shock
- rna seq
- genome wide identification
- bone marrow
- acute myeloid leukemia
- dendritic cells
- social media
- study protocol
- endoplasmic reticulum
- randomized controlled trial
- squamous cell carcinoma
- clinical trial
- type diabetes
- wild type
- immune response