1. Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.
- Author
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Gerber JP, Russ J, Chandrasekar V, Offermann N, Lee HM, Spear S, Guzzi N, Maida S, Pattabiraman S, Zhang R, Kayvanjoo AH, Datta P, Kasturiarachchi J, Sposito T, Izotova N, Händler K, Adams PD, Marafioti T, Enver T, Wenzel J, Beyer M, Mass E, Bellodi C, Schultze JL, Capasso M, Nimmo R, and Salomoni P
- Subjects
- Animals, Autoimmune Diseases genetics, Autoimmune Diseases pathology, B-Lymphocytes cytology, Cell Line, Chromatin genetics, Hematopoietic Stem Cells cytology, Histones metabolism, Humans, Inflammation pathology, Leukocyte Disorders pathology, Mice, Mice, Inbred C57BL, Mice, Knockout, Retroelements genetics, Skin Diseases genetics, Skin Diseases immunology, Skin Diseases pathology, Chromatin pathology, Co-Repressor Proteins genetics, Leukocyte Disorders congenital, Molecular Chaperones genetics, Myelopoiesis genetics, Proto-Oncogene Proteins metabolism, Trans-Activators metabolism
- 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., (© 2021. The Author(s).)
- Published
- 2021
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