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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE119309 | GEO | 2021/08/31

REPOSITORIES: GEO

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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.

Project description: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.

| S-EPMC8683376 | biostudies-literature

Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [ATAC-Seq]

Project description:The lymphoid and myeloid lineages are in equilibrium during steady-state hematopoiesis. Tilting hematopoiesis towards innate immunity has been linked to inflammation and may predispose to myeloproliferative disease. Although epigenetic players have been implicated in the control of hematopoiesis and pathogenesis of blood neoplasms, the role of chromatin-based mechanisms in regulating the lymphoid/myeloid balance remains only partially understood. Here, we show that loss of the H3.3 chaperone Daxx causes myeloid skewing, neutrophilia and pyoderma gangrenosum-like lesions, a human skin disease of unknown etiology. Daxx deficiency leads to chromatin opening at intergenic regions, including TERRA target sites, deregulation of repeat elements and activation of anti-viral defense pathways. Finally, the other main H3.3 chaperone, Hira, is dispensable for normal hematopoiesis but supports expansion of Daxx-deficient neutrophils. These results define a role for Daxx in proper selection of lymphoid versus myeloid lineages, linked to control of repeat elements and anti-inflammatory responses.

2021-08-31 | GSE119306 | GEO

Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [CUT&Tag]

Project description:Defective silencing of retroviral elements has been linked to inflamm-aging, cancer and auto-immune diseases. However, the underlying mechanisms are only partially understood. Here, we implicate the histone H3.3 chaperone Daxx, a retrotransposable element (RTE) repressor inactivated in myeloid leukemia and other neoplasms, in protection from inflammatory disease. Loss of Daxx has profound effects on chromatin landscapes and histone marks of hematopoietic progenitors, leading to engagement of a Pu.1-dependent transcriptional program for myelopoiesis at the expense of B-cell differentiation. This causes neutrophilia and inflammation, predisposing mice to development of an autoinflammatory skin disease. These molecular and phenotypic perturbations are in part reverted in animals lacking both Pu.1 and Daxx. However, hematopoietic progenitors in these mice also show unique chromatin and transcriptome alterations, suggesting synergistic interaction between the two pathways. Overall, our findings implicate RTE silencing in hematopoiesis and reveal a potential functional relationship between the H3.3 loading machinery and the pioneer transcription factor Pu.1.

2021-08-31 | GSE168367 | GEO

Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [RNA-Seq]

2021-08-31 | GSE119308 | GEO

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

Project description:Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation

| PRJNA488717 | ENA

Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [RNA-Seq]

Project description:Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [RNA-Seq]

| PRJNA488720 | ENA

Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [ATAC-Seq]

Project description:Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [ATAC-Seq]

| PRJNA488721 | ENA

Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [CUT&Tag]

Project description:Aberrant chromatin landscape upon loss of the H3.3 chaperone Daxx leads to Pu.1-mediated neutrophilia and inflammation [CUT&Tag]

| PRJNA707037 | ENA

Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation.

Project description:Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons.

| S-EPMC3657165 | biostudies-other

Structure of the variant histone H3.3-H4 heterodimer in complex with its chaperone DAXX.

Project description:Mammalian histone H3.3 is a variant of the canonical H3.1 essential for genome reprogramming in fertilized eggs and maintenance of chromatin structure in neuronal cells. An H3.3-specific histone chaperone, DAXX, directs the deposition of H3.3 onto pericentric and telomeric heterochromatin. H3.3 differs from H3.1 by only five amino acids, yet DAXX can distinguish the two with high precision. By a combination of structural, biochemical and cell-based targeting analyses, we show that Ala87 and Gly90 are the principal determinants of human H3.3 specificity. DAXX uses a shallow hydrophobic pocket to accommodate the small hydrophobic Ala87 of H3.3, whereas a polar binding environment in DAXX prefers Gly90 in H3.3 over the hydrophobic Met90 in H3.1. An H3.3-H4 heterodimer is bound by the histone-binding domain of DAXX, which makes extensive contacts with both H3.3 and H4.

| S-EPMC3932182 | biostudies-literature

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