TY  - JOUR
AU  - Gerber, Julia P
AU  - Russ, Jenny
AU  - Chandrasekar, Vijay
AU  - Offermann, Nina
AU  - Lee, Hang-Mao
AU  - Spear, Sarah
AU  - Guzzi, Nicola
AU  - Maida, Simona
AU  - Pattabiraman, Sundararaghavan
AU  - Zhang, Ruoyu
AU  - Kayvanjoo, Amir H
AU  - Datta, Preeta
AU  - Kasturiarachchi, Jagath
AU  - Sposito, Teresa
AU  - Izotova, Natalia
AU  - Händler, Kristian
AU  - Adams, Peter D
AU  - Marafioti, Teresa
AU  - Enver, Tariq
AU  - Wenzel, Jörg
AU  - Beyer, Marc-Daniel
AU  - Mass, Elvira
AU  - Bellodi, Cristian
AU  - Schultze, Joachim
AU  - Capasso, Melania
AU  - Nimmo, Rachael
AU  - Salomoni, Paolo
TI  - Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation.
JO  - Nature cell biology
VL  - 23
IS  - 12
SN  - 1465-7392
CY  - New York, NY
PB  - Nature America
M1  - DZNE-2022-00386
SP  - 1224 - 1239
PY  - 2021
AB  - 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.
KW  - Animals
KW  - Autoimmune Diseases: genetics
KW  - Autoimmune Diseases: pathology
KW  - B-Lymphocytes: cytology
KW  - Cell Line
KW  - Chromatin: genetics
KW  - Chromatin: pathology
KW  - Co-Repressor Proteins: genetics
KW  - Hematopoietic Stem Cells: cytology
KW  - Histones: metabolism
KW  - Humans
KW  - Inflammation: pathology
KW  - Leukocyte Disorders: congenital
KW  - Leukocyte Disorders: pathology
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Knockout
KW  - Molecular Chaperones: genetics
KW  - Myelopoiesis: genetics
KW  - Proto-Oncogene Proteins: metabolism
KW  - Retroelements: genetics
KW  - Skin Diseases: genetics
KW  - Skin Diseases: immunology
KW  - Skin Diseases: pathology
KW  - Trans-Activators: metabolism
KW  - Chromatin (NLM Chemicals)
KW  - Co-Repressor Proteins (NLM Chemicals)
KW  - Daxx protein, mouse (NLM Chemicals)
KW  - Histones (NLM Chemicals)
KW  - Molecular Chaperones (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - Retroelements (NLM Chemicals)
KW  - Trans-Activators (NLM Chemicals)
KW  - proto-oncogene protein Spi-1 (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34876685
C2  - pmc:PMC8683376
DO  - DOI:10.1038/s41556-021-00774-y
UR  - https://pub.dzne.de/record/163640
ER  -