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

Gerber, Julia P; Salomoni, Paolo; Beyer, Marc-Daniel; Izotova, Natalia; Händler, Kristian; Zhang, Ruoyu; Mass, Elvira; Spear, Sarah; Bellodi, Cristian; Marafioti, Teresa; Sposito, Teresa; Wenzel, Jörg; Kayvanjoo, Amir H; Capasso, Melania; Pattabiraman, Sundararaghavan; Enver, Tariq; Lee, Hang-Mao; Kasturiarachchi, Jagath; Schultze, Joachim; Adams, Peter D; Guzzi, Nicola; Datta, Preeta; Nimmo, Rachael; Chandrasekar, Vijay; Maida, Simona; Russ, Jenny; Offermann, Nina

doi:10.1038/s41556-021-00774-y

Journal Article

DZNE-2022-00386

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

Gerber, J. P. (First author)DZNE* ; Russ, J. (First author)DZNE* ; Chandrasekar, V.DZNE* ; Offermann, N.DZNE* ; Lee, H.-M.DZNE* ; Spear, S. ; Guzzi, N. ; Maida, S.DZNE* ; Pattabiraman, S.DZNE* ; Zhang, R.DZNE* ; Kayvanjoo, A. H. ; Datta, P. ; Kasturiarachchi, J. ; Sposito, T.DZNE* ; Izotova, N. ; Händler, K.DZNE* ; Adams, P. D. ; Marafioti, T. ; Enver, T. ; Wenzel, J. ; Beyer, M.-D.DZNE* ; Mass, E. ; Bellodi, C. ; Schultze, J.DZNE* ; Capasso, M.DZNE* ; Nimmo, R. ; Salomoni, P. (Last author)DZNE*

2021
Nature America New York, NY

Nature cell biology 23(12), 1224 - 1239 (2021) [10.1038/s41556-021-00774-y]

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Please use a persistent id in citations: doi:10.1038/s41556-021-00774-y

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.

Keyword(s): Animals (MeSH) ; Autoimmune Diseases: genetics (MeSH) ; Autoimmune Diseases: pathology (MeSH) ; B-Lymphocytes: cytology (MeSH) ; Cell Line (MeSH) ; Chromatin: genetics (MeSH) ; Chromatin: pathology (MeSH) ; Co-Repressor Proteins: genetics (MeSH) ; Hematopoietic Stem Cells: cytology (MeSH) ; Histones: metabolism (MeSH) ; Humans (MeSH) ; Inflammation: pathology (MeSH) ; Leukocyte Disorders: congenital (MeSH) ; Leukocyte Disorders: pathology (MeSH) ; Mice (MeSH) ; Mice, Inbred C57BL (MeSH) ; Mice, Knockout (MeSH) ; Molecular Chaperones: genetics (MeSH) ; Myelopoiesis: genetics (MeSH) ; Proto-Oncogene Proteins: metabolism (MeSH) ; Retroelements: genetics (MeSH) ; Skin Diseases: genetics (MeSH) ; Skin Diseases: immunology (MeSH) ; Skin Diseases: pathology (MeSH) ; Trans-Activators: metabolism (MeSH) ; Chromatin ; Co-Repressor Proteins ; Daxx protein, mouse ; Histones ; Molecular Chaperones ; Proto-Oncogene Proteins ; Retroelements ; Trans-Activators ; proto-oncogene protein Spi-1

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ddc:570

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Appears in the scientific report 2021

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