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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. ; Russ, Jenny ; Chandrasekar, Vijay ; Offermann, Nina ; Lee, Hang Mao ; Spear, Sarah ; Guzzi, Nicola LU ; Maida, Simona ; Pattabiraman, Sundararaghavan and Zhang, Ruoyu , et al. (2021) In Nature Cell Biology 23(12). p.1224-1239
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Cell Biology
volume
23
issue
12
pages
16 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85120802239
  • pmid:34876685
ISSN
1465-7392
DOI
10.1038/s41556-021-00774-y
language
English
LU publication?
yes
id
2b8f138f-de5e-4f02-8aa9-c94d0f7dc7cd
date added to LUP
2022-02-07 12:28:14
date last changed
2024-06-13 10:34:30
@article{2b8f138f-de5e-4f02-8aa9-c94d0f7dc7cd,
  abstract     = {{<p>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.</p>}},
  author       = {{Gerber, Julia P. and Russ, Jenny and Chandrasekar, Vijay and Offermann, Nina and Lee, Hang Mao and Spear, Sarah and Guzzi, Nicola and Maida, Simona and Pattabiraman, Sundararaghavan and Zhang, Ruoyu and Kayvanjoo, Amir H. and Datta, Preeta and Kasturiarachchi, Jagath and Sposito, Teresa and Izotova, Natalia and Händler, Kristian and Adams, Peter D. and Marafioti, Teresa and Enver, Tariq and Wenzel, Jörg and Beyer, Marc and Mass, Elvira and Bellodi, Cristian and Schultze, Joachim L. and Capasso, Melania and Nimmo, Rachael and Salomoni, Paolo}},
  issn         = {{1465-7392}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{1224--1239}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Cell Biology}},
  title        = {{Aberrant chromatin landscape following loss of the H3.3 chaperone Daxx in haematopoietic precursors leads to Pu.1-mediated neutrophilia and inflammation}},
  url          = {{http://dx.doi.org/10.1038/s41556-021-00774-y}},
  doi          = {{10.1038/s41556-021-00774-y}},
  volume       = {{23}},
  year         = {{2021}},
}