Biology subjects

Ortmann, B.

Publications and source records attributed to Ortmann, B..

3 recordsLinked to original sources

bioRxiv2025

SET1B drives sustained HIF activity and disease progression in clear cell renal cell carcinoma.

The cellular response to hypoxia is driven by hypoxia-inducible factors (HIFs), which regulate genes involved in glycolysis, angiogenesis, and cell proliferation, as well as inflammation and tumour progression. HIF activation is well-characterised and is primarily regulated by oxygen-dependent prolyl hydroxylation and subsequent degradation. However, how transcription of individual HIF target genes is regulated at the chromatin level is less clear. SET1B, a histone H3 lysine 4 (H3K4) methyltransferase, has emerged as a key modulator of HIF target gene transcription. Our study reveals that SET1B interacts with RNA Polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains. We also show that in clear cell renal cell carcinoma (ccRCC), SET1B is critical for sustained HIF activity, and SET1B expression correlates with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhances the efficacy of HIF-2 inhibitors, establishing SET1B as a potential therapeutic target in ccRCC.

cancer biology↗

bioRxiv2023

Hypoxia drives HIF2-dependent macrophage cell cycle entry and susceptibility to lentivira transduction

Macrophages play critical roles across health and disease. Low oxygen conditions (hypoxia) have been associated primarily with cell cycle arrest in cultured dividing cells. Macrophages are typically quiescent in G0, though yolk sac and bone marrow derived macrophages frequently proliferate and monocyte-derived tissue macrophages are able to proliferate in response to tissue signals. Here we show that hypoxia (1% oxygen tension) results in reversible entry into the cell cycle in monocyte derived macrophages (MDM) and mouse peritoneal macrophages. Cell cycle progression is largely limited to G1/S phase with very little progression to G2/M. Mechanistically, this cell cycle transitioning is triggered by a HIF2-directed transcriptional program. The response is accompanied by increased expression of cell cycle-associated proteins, including CDK1, and reversible activation of the canonical mitogen-activated MEK-ERK proliferation pathway. CDK1 associated SAMHD1 phosphorylation at T592 in hypoxic macrophages renders them hyper-susceptible to lentiviral transduction. Furthermore, PHD inhibitors, which activate HIFs, are able to recapitulate HIF2-dependent cell cycle entry in macrophages, as well as susceptibility to lentiviral transduction. Finally, we demonstrate that tumour associated macrophages (TAM) in lung cancers exhibit transcriptomic profiles representing responses to low oxygen and cell cycle progression at single cell level. This work uncovers HIF2 driven macrophage cell cycle progression in low oxygen conditions that culminates in SAMHD1 phosphorylation and high susceptibility to lentiviral transduction. These findings have implications for inflammation, neoplasia and pathogen defence.

cell biology↗

bioRxiv2021

Cigarette smoke preferentially induces full length ACE2 exposure in primary human airway cells but does not alter susceptibility to SARS-CoV-2 infection

Cigarette smoking has multiple serious negative health consequences. However, the epidemiological relationship between cigarette smoking and SARS-CoV-2 infection is controversial; and the interaction between cigarette smoking, airway expression of the ACE2 receptor and the susceptibility of airway cells to infection is unclear. We exposed differentiated air-liquid interface cultures derived from primary human airway stem cells to cigarette smoke extract (CSE) and infected them with SARS-CoV-2. We found that CSE increased expression of full-length ACE2 (flACE2) but did not alter the expression of a Type I-interferon sensitive truncated ACE2 that lacks the capacity to bind SARS-CoV-2 or a panel of interferon-sensitive genes. Importantly, exposure to CSE did not increase viral infectivity despite the increase in flACE2. Our data are consistent with epidemiological data suggesting current smokers are not at excess risk of SARS-CoV-2 infection. This does not detract from public health messaging emphasising the excess risk of severe COVID-19 associated with smoking-related cardiopulmonary disease.

microbiology↗