Higher promoter methylation of the Ubiquitin Associated and SH3 domain containing A (UBASH3A) gene is associated with T-lymphocyte ontogeny and reduced susceptibility to early-onset sepsis

Ziyi Wang; Nelly Amenyogbe; Rym Ben-Othman; Bing Cai; Mandy Lo; Olubukola T Idoko; Oludare A Odumade; Reza Falsafi; Travis M Blimkie; Andy An; Casey P Shannon; Sebastiano Montante; Bhavjinder K Dhillon; Joann Diray-Arce; Al Ozonoff; Kinga K Smolen; Ryan R Brinkman; Kerry McEnaney; Asimenia Angelidou; Peter Richmond; Scott J Tebbutt; Beate Kampmann; Robert E W Hancock; Amy H Y Lee; Ofer Levy; Tobias R Kollmann; David Martino

doi:10.1093/infdis/jiaf636

Higher promoter methylation of the Ubiquitin Associated and SH3 domain containing A (UBASH3A) gene is associated with T-lymphocyte ontogeny and reduced susceptibility to early-onset sepsis

J Infect Dis. 2025 Dec 17:jiaf636. doi: 10.1093/infdis/jiaf636. Online ahead of print.

Authors

Ziyi Wang^{1

2}, Nelly Amenyogbe^{3

1}, Rym Ben-Othman^{1

4}, Bing Cai⁵, Mandy Lo⁵, Olubukola T Idoko⁶, Oludare A Odumade^{7

8}, Reza Falsafi⁹, Travis M Blimkie^{10

9}, Andy An⁹, Casey P Shannon^{11

12}, Sebastiano Montante¹³, Bhavjinder K Dhillon⁹, Joann Diray-Arce^{7

8}, Al Ozonoff^{7

8

14}, Kinga K Smolen^{7

8}, Ryan R Brinkman¹³, Kerry McEnaney⁷, Asimenia Angelidou^{7

8

15}, Peter Richmond^{1

2}, Scott J Tebbutt^{11

12

16}, Beate Kampmann^{6

17}, Robert E W Hancock⁹, Amy H Y Lee¹⁰, Ofer Levy^{7

8

14}, Tobias R Kollmann^{1

3}, David Martino^{1

2}

Affiliations

¹ Kids Research Institute of Australia, 15 Hospital Avenue Nedlands, Perth 6009, WA, Australia.
² University of Western Australia, 35 Stirling Highway, Crawley,6009, WA, Australia.
³ Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax, Nova Scotia, B3H 4R2, Canada.
⁴ RAN BioLinks Ltd, 1200 Bay Street, Toronto, ON, M5R 2A5.
⁵ BC Children's Hospital, University of British Columbia, Rm 2D19, 4480 Oak Street, Vancouver, BC, V6H 3V4, Canada.
⁶ Vaccines & Immunity Theme, Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, Atlantic Boulevard, P.O. Box 273, Banjul, Gambia.
⁷ Precision Vaccines Program, Department of Pediatrics, Boston Children's Hospital, 201 Brookline Avenue, Boston, MA, 02215, USA.
⁸ Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
⁹ Department of Microbiology & Immunology, University of British Columbia, 1365-2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada.
¹⁰ Molecular Biology & Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, B.C, V5A1S6, Canada.
¹¹ PROOF Centre of Excellence, Providence Research, Vancouver, 10th Floor, 1190 Hornby Street, Vancouver, BC, V6Z 2K5, Canada.
¹² UBC Centre for Heart Lung Innovation, St. Paul's Hospital, 1081 Burrard Street, Vancouver, BC V6Z 1Y6, Canada.
¹³ BC Cancer Agency, 686 West Broadway, Suite 500 Vancouver, BC, V5Z 1G1, Canada.
¹⁴ Broad Institute of MIT and Harvard, 415 Main St, Cambridge, MA, 02142, USA.
¹⁵ Department of Neonatology, Beth Israel Deaconess Medical Centre, 330 Brookline Ave, Boston, MA 02215, USA.
¹⁶ Division of Respiratory Medicine, Department of Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver BC V6T 2B5, Canada.
¹⁷ Centre for Global Health and Institute for International Health, Charite Universitatsmedizin, Augustenburger Platz 1, Berlin, 13353, Germany.

PMID: 41408597
DOI: 10.1093/infdis/jiaf636

Abstract

We investigated the genetic and epigenetic regulation of the UBASH3A gene and its association with early-onset sepsis. Using matched whole blood DNA methylation, gene expression, genotypes and immune cell counts from the EPIC-HIPC newborn cohort, we report promoter methylation was negatively correlated (Pearson's r = -0.5, p < 2.2×10-16) with ontogenetic changes in UBASH3A gene expression and circulating CD3+ T-cell numbers. Higher promoter methylation at birth was associated with lower UBASH3A expression and reduced early onset sepsis risk (OR = 0.26, p = 0.015). Genetic variation significantly influenced variations in baseline UBASH3A methylation (132 cis-meQTL, FDR < 0.05).

Keywords: DNA methylation; Neonatal sepsis; UBASH3A; ontogeny.