Aberrant Chromatin Landscape Following Loss of the H3.3 Chaperone Daxx in Haematopoietic Precursors Leads to Pu.1-mediated Neutrophilia and Inflammation

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2021 Dec 8

PMID 34876685

Citations 10

Authors

Julia P Gerber

Jenny Russ

Vijay Chandrasekar

Nina Offermann

Hang-Mao Lee

Sarah Spear

Nicola Guzzi

Simona Maida

Sundararaghavan Pattabiraman

Ruoyu Zhang

Amir H Kayvanjoo

Preeta Datta

Jagath Kasturiarachchi

Teresa Sposito

Natalia Izotova

Kristian Handler

Peter D Adams

Teresa Marafioti

Tariq Enver

Jorg Wenzel

Marc Beyer

Elvira Mass

Cristian Bellodi

Joachim L Schultze

Melania Capasso

Rachael Nimmo

Paolo Salomoni

Affiliations

Soon will be listed here.

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.

Citing Articles

Histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers.

Kazerani M, Cernilogar F, Pasquarella A, Hinterberger M, Nuber A, Klein L Proc Natl Acad Sci U S A. 2024; 121(52):e2409656121.

PMID: 39689172 PMC: 11670114. DOI: 10.1073/pnas.2409656121.

Stem cell activity-coupled suppression of endogenous retrovirus governs adult tissue regeneration.

Lyu Y, Kim S, Humphrey E, Nayak R, Guan Y, Liang Q Cell. 2024; 187(26):7414-7432.e26.

PMID: 39476839 PMC: 11682924. DOI: 10.1016/j.cell.2024.10.007.

Plasma cell differentiation is regulated by the expression of histone variant H3.3.

Saito Y, Harada A, Ushijima M, Tanaka K, Higuchi R, Baba A Nat Commun. 2024; 15(1):5004.

PMID: 38902223 PMC: 11190180. DOI: 10.1038/s41467-024-49375-x.

HIRA vs. DAXX: the two axes shaping the histone H3.3 landscape.

Choi J, Kim T, Cho E Exp Mol Med. 2024; 56(2):251-263.

PMID: 38297159 PMC: 10907377. DOI: 10.1038/s12276-023-01145-3.

(B)On(e)-cohistones and the epigenetic alterations at the root of bone cancer.

Salomoni P, Flanagan A, Cottone L Cell Death Differ. 2023; 32(1):66-77.

PMID: 37828086 PMC: 11748643. DOI: 10.1038/s41418-023-01227-9.

References

Kunarso G, Chia N, Jeyakani J, Hwang C, Lu X, Chan Y . Transposable elements have rewired the core regulatory network of human embryonic stem cells. Nat Genet. 2010; 42(7):631-4. DOI: 10.1038/ng.600. View

Chuong E, Rumi M, Soares M, Baker J . Endogenous retroviruses function as species-specific enhancer elements in the placenta. Nat Genet. 2013; 45(3):325-9. PMC: 3789077. DOI: 10.1038/ng.2553. View

Mita P, Boeke J . How retrotransposons shape genome regulation. Curr Opin Genet Dev. 2016; 37:90-100. PMC: 4914423. DOI: 10.1016/j.gde.2016.01.001. View

Volkman H, Stetson D . The enemy within: endogenous retroelements and autoimmune disease. Nat Immunol. 2014; 15(5):415-22. PMC: 4131434. DOI: 10.1038/ni.2872. View

Tugnet N, Rylance P, Roden D, Trela M, Nelson P . Human Endogenous Retroviruses (HERVs) and Autoimmune Rheumatic Disease: Is There a Link?. Open Rheumatol J. 2013; 7:13-21. PMC: 3636489. DOI: 10.2174/1874312901307010013. View

Gonzalez-Cao M, Iduma P, Karachaliou N, Santarpia M, Blanco J, Rosell R . Human endogenous retroviruses and cancer. Cancer Biol Med. 2017; 13(4):483-488. PMC: 5250606. DOI: 10.20892/j.issn.2095-3941.2016.0080. View

Downey R, Sullivan F, Wang-Johanning F, Ambs S, Giles F, Glynn S . Human endogenous retrovirus K and cancer: Innocent bystander or tumorigenic accomplice?. Int J Cancer. 2014; 137(6):1249-57. PMC: 6264888. DOI: 10.1002/ijc.29003. View

Manghera M, Ferguson-Parry J, Lin R, Douville R . NF-κB and IRF1 Induce Endogenous Retrovirus K Expression via Interferon-Stimulated Response Elements in Its 5' Long Terminal Repeat. J Virol. 2016; 90(20):9338-49. PMC: 5044829. DOI: 10.1128/JVI.01503-16. View

Groh S, Schotta G . Silencing of endogenous retroviruses by heterochromatin. Cell Mol Life Sci. 2017; 74(11):2055-2065. PMC: 11107624. DOI: 10.1007/s00018-017-2454-8. View

10.

He Q, Kim H, Huang R, Lu W, Tang M, Shi F . The Daxx/Atrx Complex Protects Tandem Repetitive Elements during DNA Hypomethylation by Promoting H3K9 Trimethylation. Cell Stem Cell. 2015; 17(3):273-86. PMC: 4571182. DOI: 10.1016/j.stem.2015.07.022. View

11.

Elsasser S, Noh K, Diaz N, Allis C, Banaszynski L . Histone H3.3 is required for endogenous retroviral element silencing in embryonic stem cells. Nature. 2015; 522(7555):240-244. PMC: 4509593. DOI: 10.1038/nature14345. View

12.

Qadeer Z, Valle-Garcia D, Hasson D, Sun Z, Cook A, Nguyen C . ATRX In-Frame Fusion Neuroblastoma Is Sensitive to EZH2 Inhibition via Modulation of Neuronal Gene Signatures. Cancer Cell. 2019; 36(5):512-527.e9. PMC: 6851493. DOI: 10.1016/j.ccell.2019.09.002. View

13.

Lewis P, Elsaesser S, Noh K, Stadler S, Allis C . Daxx is an H3.3-specific histone chaperone and cooperates with ATRX in replication-independent chromatin assembly at telomeres. Proc Natl Acad Sci U S A. 2010; 107(32):14075-80. PMC: 2922592. DOI: 10.1073/pnas.1008850107. View

14.

Goldberg A, Banaszynski L, Noh K, Lewis P, Elsaesser S, Stadler S . Distinct factors control histone variant H3.3 localization at specific genomic regions. Cell. 2010; 140(5):678-91. PMC: 2885838. DOI: 10.1016/j.cell.2010.01.003. View

15.

Drane P, Ouararhni K, Depaux A, Shuaib M, Hamiche A . The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3. Genes Dev. 2010; 24(12):1253-65. PMC: 2885661. DOI: 10.1101/gad.566910. View

16.

Ray-Gallet D, Ricketts M, Sato Y, Gupta K, Boyarchuk E, Senda T . Functional activity of the H3.3 histone chaperone complex HIRA requires trimerization of the HIRA subunit. Nat Commun. 2018; 9(1):3103. PMC: 6078998. DOI: 10.1038/s41467-018-05581-y. View

17.

Lara-Astiaso D, Weiner A, Lorenzo-Vivas E, Zaretsky I, Jaitin D, David E . Immunogenetics. Chromatin state dynamics during blood formation. Science. 2014; 345(6199):943-9. PMC: 4412442. DOI: 10.1126/science.1256271. View

18.

Pundhir S, Lauridsen F, Schuster M, Jakobsen J, Ge Y, Schoof E . Enhancer and Transcription Factor Dynamics during Myeloid Differentiation Reveal an Early Differentiation Block in Cebpa null Progenitors. Cell Rep. 2018; 23(9):2744-2757. DOI: 10.1016/j.celrep.2018.05.012. View

19.

Nguyen D, Voon H, Xella B, Scott C, Clynes D, Babbs C . The chromatin remodelling factor ATRX suppresses R-loops in transcribed telomeric repeats. EMBO Rep. 2017; 18(6):914-928. PMC: 5452009. DOI: 10.15252/embr.201643078. View

20.

Redon S, Reichenbach P, Lingner J . The non-coding RNA TERRA is a natural ligand and direct inhibitor of human telomerase. Nucleic Acids Res. 2010; 38(17):5797-806. PMC: 2943627. DOI: 10.1093/nar/gkq296. View