Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity
| Title: | Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity |
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| Authors: | Sanchez-Garcia, MA; Sadiku, P; Ortmann, BM; Wit, N; Negishi, Y; Coelho, P; Zhang, A; Pednekar, C; Howden, AJM; Griffith, DM; Seear, R; Kindrick, JD; Mengede, J; Cooper, G; Morrison, T; Watts, ER; Shimeld, BT; Reyes, L; Mirchandani, AS; Arienti, S; Xu, X; Thomson, A; Brenes, AJ; Turton, HA; Dowey, R; Hull, RC; Davidson-Smith, H; McLaren, A; Deans, A; Choudhury, G; Doverman, K; Hope, D; Vick, O; Woodhead, A; Petrie, I; Green, S; Rzechorzek, NM; Turtle, L; Openshaw, PJM; Semple, MG; Sproul, D; Baillie, JK; Thompson, AAR; Mole, DR; von Kriegsheim, A; Whyte, MKB; Mhalanga, MM; Nathan, JA; Walmsley, SR |
| Publisher Information: | Springer Science and Business Media LLC |
| Publication Year: | 2025 |
| Collection: | The University of Liverpool Repository |
| Description: | The long-term impact of systemic hypoxia resulting from acute respiratory distress syndrome (ARDS) on the function of short-lived innate immune cells is unclear. We show that patients 3–6 months after recovering from ARDS have persistently impaired circulating neutrophil effector functions and an increased susceptibility to secondary infections. These defects are linked to a widespread loss of the activating histone mark H3K4me3 in genes that are crucial for neutrophil activities. By studying healthy volunteers exposed to altitude-induced hypoxemia, we demonstrate that oxygen deprivation alone causes this long-term neutrophil reprogramming. Mechanistically, mouse models of systemic hypoxia reveal that persistent loss of H3K4me3 originates in proNeu and preNeu progenitors within the bone marrow and is linked to N-terminal histone 3 clipping, which removes the lysine residue for methylation. Thus, we present new evidence that systemic hypoxia initiates a sustained maladaptive reprogramming of neutrophil immunity by triggering histone 3 clipping and H3K4me3 loss in neutrophil progenitors. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 1529-2908 |
| Relation: | https://livrepository.liverpool.ac.uk/3196647/1/Hypoxia%20induces%20histone%20clipping%20and%20H3K4me3%20loss%20in%20neutrophil%20progenitors%20resulting%20in%20long-term%20impairment%20of%20neutrophil%20.pdf; Collapse authors list. Sanchez-Garcia, MA orcid:0000-0003-3914-2332 , Sadiku, P, Ortmann, BM, Wit, N, Negishi, Y, Coelho, P, Zhang, A, Pednekar, C, Howden, AJM orcid:0000-0002-4332-9469 , Griffith, DM orcid:0000-0001-9500-241X et al (show 39 more authors) , Seear, R, Kindrick, JD, Mengede, J, Cooper, G, Morrison, T orcid:0000-0002-3432-579X , Watts, ER, Shimeld, BT, Reyes, L, Mirchandani, AS orcid:0000-0002-5492-1687 , Arienti, S orcid:0000-0002-5406-0012 , Xu, X orcid:0009-0009-9282-2098 , Thomson, A, Brenes, AJ orcid:0000-0001-8298-2463 , Turton, HA, Dowey, R orcid:0000-0002-2389-9114 , Hull, RC, Davidson-Smith, H, McLaren, A, Deans, A, Choudhury, G, Doverman, K, Hope, D, Vick, O orcid:0000-0003-0722-6611 , Woodhead, A, Petrie, I orcid:0009-0002-7700-6307 , Green, S orcid:0009-0007-6249-5714 , Rzechorzek, NM orcid:0000-0003-3209-5019 , Turtle, L, Openshaw, PJM orcid:0000-0002-7220-2555 , Semple, MG orcid:0000-0001-9700-0418 , Sproul, D, Baillie, JK orcid:0000-0001-5258-793X , Thompson, AAR orcid:0000-0002-0717-4551 , Mole, DR orcid:0000-0002-0984-300X , von Kriegsheim, A orcid:0000-0002-4952-8573 , Whyte, MKB orcid:0000-0001-7788-1852 , Mhalanga, MM orcid:0000-0003-1381-3409 , Nathan, JA orcid:0000-0002-0248-1632 and Walmsley, SR orcid:0000-0001-9584-174X (2025) Hypoxia induces histone clipping and H3K4me3 loss in neutrophil progenitors resulting in long-term impairment of neutrophil immunity Nature Immunology, 26 (11). pp. 1903-1915. ISSN 1529-2908, 1529-2916 |
| DOI: | 10.1038/s41590-025-02301-9 |
| Availability: | https://livrepository.liverpool.ac.uk/3196647/; https://doi.org/10.1038/s41590-025-02301-9 |
| Rights: | cc_by_4 |
| Accession Number: | edsbas.401A7266 |
| Database: | BASE |