Biology subjects

Meier, S.

Publications and source records attributed to Meier, S..

At least 19 recordsLinked to original sources

bioRxiv2025

An Engineered Living Material with pro-angiogenic activity inducible by near-infrared light

Impaired angiogenesis is a central barrier in the treatment of chronic and deep tissue wounds, preventing progression through the normal healing cascade. While the combination of near-infrared (NIR) photobiomodulation and pro-angiogenic growth factors has shown synergistic therapeutic benefit, the clinical translation of growth factor therapy is hindered by high cost, instability and the need for localized dosing to avoid aberrant vasculature. Peptidomimetics such as the VEGF-derived QK peptide offer a more stable and predictable alternative, but still require a means for localized, tunable presentation. Here, we establish an engineered living material based delivery system that responds to clinically relevant NIR light to produce and releases a QK-Fusion protein directly at the target site. The probiotic Escherichia coli Nissle 1917 was engineered with an 800 nm-responsive optogenetic circuit and encapsulated within an optimized alginate core-shell hydrogel that ensures biocontainment while allowing controlled outward diffusion of the secreted peptide. The released peptide remains non-cytotoxic and capable of binding extracellular matrix analogs and promoting the formation of organized, branched capillary-like networks in endothelial cultures. We thus establish a strategy for developing engineered living materials towards remote-controlled angiogenic stimulation.

bioengineering↗

bioRxiv2025

Comprehensively Testing the Function of Missense Variation in the STK11 Tumour Suppressor

The tumor suppressor gene STK11 encoding Serine/Threonine Kinase 11 (STK11) is associated with Peutz-Jeghers Syndrome (PJS), a heritable gastrointestinal disease that increases lifetime cancer risk, and with somatic variation that contributes to [~]30% of lung and 20% of cervical cancers. Although identifying pathogenic variants is clinically actionable, over 94% of STK11 missense variants that have been observed clinically lack a definitive classification. We therefore measured the impact of STK11 variants at scale in a mammalian cell-based assay, scoring 6,026 (73% of all possible) amino acid substitutions across the full-length gene. Functional scores--which were consistent with biochemical properties, smaller-scale assays, and pathogenicity annotations--identified a subset of PJS patients with germline STK11 variants diagnosed later in life, as well as somatic STK11 variants found in cancer patients that had comparable overall survival estimates to wild-type STK11. Our scores provided new evidence for 350 annotated VUS STK11 missense variants and [~]80% of missense variants that have not yet been reported clinically, but we might expect to observe in the future. Thus, our effect map provides a proactive resource for gaining sequence-structure-function insights and evidence for actionable interpretation of clinical missense variants.

cancer biology↗

bioRxiv2024

Back to the horns: a reconstruction of the ancestral horn state through distinct types of recombination events.

BackgroundBreeding of the genetically polled animals is the desirable approach in modern cattle husbandry. At least four different genetic variants associated with polledness in cattle have been identified, suggesting genetic heterogeneity. These dominant variants have been identified on chromosome 1 between the regions of approx. 2.42 to 2.73 Mb (reference: ARS-UCD1.2), also called the POLLED locus. Among these variants, Friesian (PF, 80 kbp duplication) and Celtic (PC, 212 bp complex InDel) are the most observed in the majority of breeds in the production systems globally, such as in Holstein-Friesian (HF) and Fleckvieh (FV). While a putative causal association of PC with polledness is proven, the presence of large duplication in PF makes it difficult to prove the causality. ResultsIn this study, we conduct whole-genome sequencing (WGS) analysis of two trios exhibiting unexpected inheritance patterns related to PC and PF variants. In both instances, horned offspring were produced from mating pairs where one parent was homozygous for the polled variant, and the other was homozygous for the ancestral horned variant. By analyzing the WGS data generated using long-read sequence technology, we show that de-novo generation of the ancestral horned variant in both the offspring was the result of distinct recombination events. Specifically, in case of the HF trio, it was the result of non-allelic homologous recombination in the gametes of the sire (PF/PF), while in case of the FV trio, it was the result of allelic homologous recombination in the gametes of the dam (PC/PF). The findings from the HF trio support the hypothesis that the 80-kbp duplication is the genetic variant responsible for the polled phenotype of Friesian origin. ConclusionHere we show that different genomic arrangements in POLLED locus can lead to the emergence of de-novo ancestral horn phenotypes. These kinds of arrangements can make a reliable gene test less reliable and the derivation of the phenotype difficult to predict. Therefore, it is important for the large POLLED-locus that any deviation from the expected result is critically analyzed. Possibly some of these cases can further narrow down the sequence motif that is essential for polledness in cattle.

genomics↗

bioRxiv2024

Mechanical problem solving in mice

Behavioral learning is a complex phenomenon that involves cognitive, perceptual, motor and emotional contributions. Yet, most animal studies focus on reductionist tasks that aim to isolate one of these aspects [1, 2, 3, 4]. Here, we use a lockbox -- a complex, multi-step mechanical puzzle -- to study learning dynamics in freely behaving mice. The mice engaged spontaneously with the task and learned to solve it within just a few trials. To dissect different contributions to this rapid form of learning, we combined deep learning-based behavioral tracking in a multi-camera setup with probabilistic inference and computational modeling. We find that the learning progress of the mice was initially dominated by the acquisition of motor skills, i.e., the increased ability to manipulate the individual mechanisms, while a cognitive strategy for the task sequence emerged only later. The lockbox paradigm may hence offer a promising framework for studying the interaction between low-level motor learning and high-level decision-making strategies in a single, ethologically relevant task.

animal behavior and cognition↗

bioRxiv2024

An arrayed CRISPR/Cas9 screen identifies mTORC1 as a regulator of lipid droplet accumulation in APOE E3 and APOE KO iPSC-derived microglia

Variants of the Apolipoprotein E (APOE) gene, particularly the E4 allele, are significantly associated with an increased risk of Alzheimers Disease and have been implicated in neuroinflammatory processes due to disrupted lipid metabolism. Lipid alterations can manifest in glial cells as an excessive buildup of lipids, potentially contributing to neuroinflammation. In this study, we observed a heightened lipid load in APOE-deficient human induced pluripotent stem cell (iPSC)-derived microglia relative to cells with other APOE isoforms. To explore the mechanisms governing lipid handling within microglia, we established a technique for the nucleofection of CRISPR/Cas9 ribonucleoprotein complexes into iPSC-derived myeloid cells. Utilizing this method, we performed a targeted screen to identify key upstream modifiers in lipid droplet formation. Our findings highlight the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway as a pivotal influence on lipid storage in microglia with both APOE3 and APOE knockout genotypes, underscoring its role in lipid dysregulation associated with Alzheimers Disease and neuroinflammation.

neuroscience↗

bioRxiv2023

Not seeing the forest for the trees: Combination of path integration and landmark cues in human virtual navigation

IntroductionIn order to successfully move from place to place, our brain often combines sensory inputs from various sources by dynamically weighting spatial cues according to their reliability and relevance for a given task. Two of the most important cues in navigation are the spatial arrangement of landmarks in the environment, and the continuous path integration of travelled distances and changes in direction. Several studies have shown that Bayesian integration of cues provides a good explanation for navigation in environments dominated by small numbers of easily identifiable landmarks. However, it remains largely unclear how cues are combined in more complex environments. MethodsTo investigate how humans process and combine landmarks and path integration in complex environments, we conducted a series of triangle completion experiments in virtual reality, in which we varied the number of landmarks from an open steppe to a dense forest, thus going beyond the spatially simple environments that have been studied in the past. We analysed spatial behaviour at both the population and individual level with linear regression models and developed a computational model, based on maximum likelihood estimation (MLE), to infer the underlying combination of cues. ResultsOverall homing performance was optimal in an environment containing three landmarks arranged around the goal location. With more than three landmarks, individual differences between participants in the use of cues are striking. For some, the addition of landmarks does not worsen their performance, whereas for others it seems to impair their use of landmark information. DiscussionIt appears that navigation success in complex environments depends on the ability to identify the correct clearing around the goal location, suggesting that some participants may not be able to see the forest for the trees.

neuroscience↗

bioRxiv2023

Inosine Induces Stemness Features in CAR T cells and Enhances Potency

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8+ CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness. INO induced a profound metabolic reprogramming, diminishing glycolysis and increasing oxidative phosphorylation, glutaminolysis and polyamine synthesis, and modulated the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR T cell products meeting criteria for clinical dosing. These data identify INO as a potent modulator of T cell metabolism and epigenetic stemness programming and deliver a new enhanced potency platform for immune cell manufacturing. Statement of SignificanceAdenosine is well known to inhibit T cell function and substantial effort has focused on inhibiting adenosine generation and signaling. Here, we show that exhausted T cells are suppressed by adenosine, which is only modestly impacted by inhibiting adenosine generation or signaling. In contrast, metabolism of adenosine to inosine augmented T cell function and culture of T cells with inosine induced multi-level reprogramming leading to stemness and improved anti-tumor potency. We demonstrate the feasibility of introducing inosine during GMP cell manufacturing as a novel strategy to generate enhanced CAR-T cells.

immunology↗

bioRxiv2022

Sialidases and Fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria

The gut mucolytic specialist Akkermansia muciniphila is strongly associated with the integrity of the mucus layer. Mucin glycan utilization requires the removal of diverse protective caps, notably, fucose and sialic acid, but the enzymatic details of this process remain largely unknown. Here, we describe the specificities of ten A. muciniphila glycoside hydrolases, which collectively remove all known sialyl and fucosyl mucin caps including those with double sulphated epitopes. Structural analyses revealed an unprecedented fucosidase modular arrangement and explained the exclusive sialyl T-antigen specificity of a sialidase of a previously unknown family and catalytic apparatus. Key cell attached sialidases and fucosidases conferred mucin-binding and their inhibition abolished growth of A. muciniphila on mucin. Remarkably, the sialic acid fucose did not contribute to A. muciniphila growth, but instead promoted butyrate production by co-cultured Clostridia. This study brings unique mechanistic insight into the initiation of mucin O-glycan degradation by A. muciniphila and the nutrient sharing between key mucus-associated bacteria.

biochemistry↗

bioRxiv2022

Identification of a cardiac glycoside exhibiting favorable brain bioavailability and potency for reducing levels of the cellular prion protein

Several strands of investigation have established that a reduction in the levels of the cellular prion protein (PrPC) is a promising avenue for the treatment of prion diseases. We recently described an indirect approach for reducing PrPC levels that targets Na,K-ATPases (NKAs) with cardiac glycosides (CGs), causing cells to respond with the degradation of these pumps and nearby molecules, including PrPC. Because the therapeutic window of widely used CGs is narrow and their brain bioavailability is low, we set out to identify a CG with improved pharmacological properties for this indication. Starting with the CG known as oleandrin, we combined in silico modeling of CG binding poses within human NKA folds, CG structure-activity relationship (SAR) data, and predicted blood-brain barrier (BBB) penetrance scores to identify CG derivatives with improved characteristics. Focusing on C4-dehydro-oleandrin as a chemically accessible shortlisted CG derivative, we show that it reaches four times higher levels in the brain than in the heart one day after subcutaneous administration, exhibits promising pharmacological properties, and suppresses steady-state PrPC levels by 84% in immortalized human cells that have been differentiated to acquire neural or astrocytic characteristics. Finally, we validate that the mechanism of action of this approach for reducing cell surface PrPC levels requires C4-dehydro-oleandrin to engage with its cognate binding pocket within the NKA subunit. The improved brain bioavailability of C4-dehydro-oleandrin, combined with its relatively low toxicity, make this compound an attractive lead for brain CG indications and recommends its further exploration for the treatment of prion diseases. AUTHOR SUMMARYPrion diseases are fatal neurodegenerative diseases for which there is no effective treatment. An abundance of data indicates that reducing the levels of a specific protein, termed the cellular prion protein (PrPC), would not only be safe but would delay disease onset and extend prion disease survival. This project builds on our recent discovery that PrPC binds to NKAs, specific cellular transport proteins that use energy to electrify cellular membranes by pumping charged potassium and sodium metals in and out of cells. We showed that targeting NKAs with their natural inhibitors, cardiac glycosides (CGs), causes brain cells to internalize and degrade NKAs, and that PrPC, on account of residing next to NKAs, gets co-degraded. Natural CGs act primarily on the heart. Here, we used computational modeling to identify a CG, termed KDC203, that is predicted to have favorable characteristics for brain applications. We show that KDC203 reduces PrPC levels by 84% in immortalized human brain-like cells grown in the dish. Moreover, we show that KDC203 exhibits relatively low toxicity, predominantly targets the brain when subcutaneously injected into mice, and has other promising pharmacological characteristics that recommend it for further evaluation for the treatment of prion diseases.

neuroscience↗

bioRxiv2022

Neutrophil degranulation, NETosis and platelet degranulation pathway genes are co-induced in whole blood up to six months before tuberculosis diagnosis

Mycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Host immune responses have been implicated in driving the progression from infection to severe lung disease. We analyzed longitudinal RNA sequencing (RNAseq) data from the whole blood of 74 TB progressors whose samples were grouped into four six-month intervals preceding diagnosis (the GC6-74 study). We additionally analyzed RNAseq data from an independent cohort of 90 TB patients with positron emission tomography-computed tomography (PET-CT) scan results which were used to categorize them into groups with high and low levels of lung damage (the Catalysis TB Biomarker study). These groups were compared to non-TB controls to obtain a complete whole blood transcriptional profile for individuals spanning from early stages of M.tb infection to TB diagnosis. The results revealed a steady increase in the number of genes that were differentially expressed in progressors at time points closer to diagnosis with 278 genes at 13-18 months, 742 at 7-12 months and 5,131 detected 1-6 months before diagnosis and 9,205 detected in TB patients. A total of 2,144 differentially expressed genes were detected when comparing TB patients with high and low levels of lung damage. There was a large overlap in the genes upregulated in progressors 1-6 months before diagnosis (86%) with those in TB patients. A comprehensive pathway analysis revealed a potent activation of neutrophil and platelet mediated defenses including neutrophil and platelet degranulation, and NET formation at both time points. These pathways were also enriched in TB patients with high levels of lung damage compared to those with low. These findings suggest that neutrophils and platelets play a critical role in TB pathogenesis, and provide details of the timing of specific effector mechanisms that may contribute to TB lung pathology. Author summaryMycobacterium tuberculosis (M.tb) causes tuberculosis (TB) and remains one of the leading causes of mortality due to an infectious pathogen. Human immune responses must be balanced to inhibit disease progression while limiting self-damage, however in defense against M.tb host responses have been implicated in lung damage and in driving progression of M.tb infection to severe lung disease. The identification of immune responses that are activated during the development of TB could provide potential targets for interventions that might suppress disease progression, and possibly limit tissue damage. Here we identify a subset of genes that function in several biological processes that are strongly activated in the late stages of TB development and in TB patients. The proteins encoded by these genes are known to degrade lung tissue and contribute to severe lung disease.

genomics↗

bioRxiv2021

Reversible supramolecular assembly of the anti-microbial peptide plectasin into helical non-amyloid fibrils

Self-assembly and fibril formation play important roles in protein behavior. Amyloid fibrils formation is well-studied due to its role in neurodegenerative diseases and characterized by refolding of the protein into predominant {beta}-sheet form. However, much less is known about the assembly of proteins into other types of supramolecular structures. Using cryo-electron microscopy at a resolution of 1.97 [A], we show that a triple-mutant of the anti-microbial peptide plectasin assembles reversibly into helical non-amyloid fibrils. Plectasin contains a cysteine-stabilized -helix-{beta}-sheets structure, which remains intact upon fibril formation. Two fibrils form a right-handed superstructure with each fibril consisting of double helical, left-handed structures. The fibril formation is reversible and follows sigmoidal kinetics with a pH-dependent equilibrium between soluble monomer and protein fibril. The anti-microbial activity does not appear compromised by fibril formation. This is the first high-resolution structure of this type of /{beta} protein fibrils.

biophysics↗

bioRxiv2021

Cardiac dysfunction affects eye development and vision by reducing supply of lipids in fish

Developing organisms are especially vulnerable to environmental stressors. We aimed to understand the underlying mechanisms of phenanthrene (Phe) and crude oil induced eye malformations. We exposed Atlantic haddock (Melanogrammus aeglefinus) embryos to a known L-type calcium channel blocker, nicardipine hydrochloride (Nic), and compared to early embryonic crude oil (Oil) and late embryonic Phe toxicity. All treatments lead to severe, eye, jaw and spinal deformities at early larval stages. At 3 days post hatching, larvae from all treatments and corresponding controls were dissected. Eyes, trunk, head and yolk sac were subjected to lipid profiling, and eyes were also subjected to transcriptomic profiling. Changes in lipid profiles and the transcriptome suggested that the dysfunctional and abnormal eyes in our treatments were due to both disruption of signaling pathways and insufficient supply of essential fatty acids and other nutrients form the yolk.

molecular biology↗

bioRxiv2020

Massive X-ray screening reveals two allosteric drug binding sites of SARS-CoV-2 main protease

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous health problems and economical challenges for mankind. To date, no effective drug is available to directly treat the disease and prevent virus spreading. In a search for a drug against COVID-19, we have performed a massive X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for the virus replication and, thus, a potent drug target. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds binding to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and five non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.

biophysics↗

bioRxiv2020

Untangling mechanisms of crude oil toxicity in a cold water fish via gene expression, morphology and PAHs at two developmental stages

Early life stages of fish are highly sensitive to crude oil exposure and thus, short term exposures during critical developmental periods could have detrimental consequences for juvenile survival. Here we administered crude oil to Atlantic haddock (Melanogrammus aeglefinus) in short term (3-day) exposures at two developmental time periods: before first heartbeat, from gastrulation to cardiac cone stage (early), and from first heartbeat to one day before hatching (late). A frequent sampling regime enabled us to determine immediate PAH uptake, metabolite formation and gene expression changes. In general, the embryotoxic consequences of an oil exposure were more severe in the early exposure animals. Oil droplet fouling in the highest doses resulted in severe cardiac and craniofacial abnormalities. Gene expression changes of Cytochrome 1 a,b,c and d (cyp1a,b,c,d), Bone morphogenetic protein 10 (bmp10), ABC transporter b1 (abcb1) and Rh-associated G-protein (rhag) were linked to PAH uptake, occurrence of metabolites of phenanthrene and developmental and functional abnormalities. We detected circulation-independent, oil-induced gene expression changes and separated phenotypes linked to proliferation, growth and disruption of formation events at early and late developmental stages. Our study gives an increased knowledge about developmentally dependent effects of crude oil toxicity. Thus, providing more knowledge and detail to new and several existing adverse outcome pathways of crude oil toxicity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/288852v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@106fe07org.highwire.dtl.DTLVardef@f8d7borg.highwire.dtl.DTLVardef@1118852org.highwire.dtl.DTLVardef@ccc59_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIOil droplet fouling occurred in the whole water column and increased the oil toxicity. C_LIO_LIEarly exposure resulted in higher PAH uptake due to lower metabolism resulting in more severe abnormalities. C_LIO_LIA rapid and circulation-indepenent regulation of bmp10 suggested a direct oil-induced effect on calcium homeostasis. C_LIO_LIExpression of rhag indicated a direct oil-induced effect on osmoregulatory cells and osmoregulation. C_LIO_LISevere eye abnormalities especially in the late exposure was linked to inappropriate overexpression of cyp1b in the eyes. C_LI

biochemistry↗

bioRxiv2020

Serial femtosecond and serial synchrotron crystallography yield data of equivalent quality: a systematic comparison

For the two proteins myoglobin (MB) and fluoroacetate dehalogenase (FAcD), we present a systematic comparison of crystallographic diffraction data collected by serial femtosecond (SFX) and serial synchrotron crystallography (SSX). To maximize comparability, we used the same batch of crystals, the same sample delivery device, as well as the same data analysis software. Overall figures of merit indicate that the data of both radiation sources are of equivalent quality. For both proteins reasonable data statistics can be obtained with approximately 5000 room temperature diffraction images irrespective of the radiation source. The direct comparability of SSX and SFX data indicates that diffraction quality is rather linked to the properties of the crystals than to the radiation source. Time-resolved experiments can therefore be conducted at the source that best matches the desired time-resolution.

biophysics↗

bioRxiv2020

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.

biophysics↗

bioRxiv2019

Socio-behavioural characteristics and HIV: findings from a causal modelling analysis of 29 sub-Saharan African countries

IntroductionSocio-behavioural factors may contribute to the wide variance in HIV prevalence between and within sub-Saharan African (SSA) countries. We studied the associations between socio-behavioural variables potentially related to the risk of acquiring HIV. MethodsWe used Bayesian network models to study associations between socio-behavioural variables that may be related to HIV. A Bayesian network consists of nodes representing variables, and edges representing the conditional dependencies between variables. We analysed data from Demographic and Health Surveys conducted in 29 SSA countries between 2010 and 2016. We predefined and dichotomized twelve variables, including factors related to age, literacy, HIV knowledge, HIV testing, domestic violence, sexual activity, and womens empowerment. We analysed data on men and women for each country separately and then summarised the results across the countries. We conducted a second analysis including also the individual HIV status in a subset of 23 countries where this information was available. We presented summary graphs showing associations that were present in at least six countries (five in the analysis with HIV status). ResultsWe analysed data from 190,273 men (range across countries 2,295-17,359) and 420,198 women (6,621-38,948). The two variables with the highest total number of edges in the summary graphs were literacy and rural/urban location. Literacy was negatively associated with false beliefs about AIDS and, for women, early sexual initiation, in most countries. Literacy was also positively associated with ever being tested for HIV and the belief that women have the right to ask their husband to use condoms if he has a sexually transmitted infection. Rural location was positively associated with false beliefs about HIV and the belief that beating ones wife is justified, and negatively associated with having been tested for HIV. In the analysis including HIV status, being HIV positive was associated with female-headed household, older age and rural location among women, and with no variables among men. ConclusionsLiteracy and urbanity were strongly associated with several factors that are important for HIV acquisition. Since literacy is one of the few variables that can be improved by interventions, this makes it a promising intervention target.

epidemiology↗

bioRxiv2019

The UTX Tumor Suppressor Directly Senses Oxygen to Control Chromatin and Cell Fate

Mammalian cells express multiple 2-oxoglutarate (OG)-dependent dioxygenases, including many chromatin regulators. The oxygen affinities, and hence oxygen sensing capabilities, of the 2-oxoglutarate (OG)-dependent dioxygenases reported to date vary widely. Hypoxia can affect chromatin, but whether this reflects a direct effect on chromatin-modifying dioxygenases, or indirect effects caused by the hypoxic-induction of the HIF transcription factor or the endogenous 2-OG competitor 2-hydroxyglutarate (2-HG), is unclear. Here we report that hypoxia induces a HIF- and 2-HG-independent histone modification signature consistent with KDM inactivation. We also show that the H3K27 histone demethylase KDM6A (also called UTX), but not its paralog KDM6B, is oxygen-sensitive. KDM6A loss, like hypoxia, prevented H3K27me3 erasure and blocked differentiation. Conversely, restoring H3K27me3 homeostasis in hypoxic cells reversed these effects. Therefore, oxygen directly affects chromatin regulators to control cell fate.\n\nOne Sentence SummaryKDM6A demethylase activity is diminished under hypoxic conditions and causes changes in gene expression programs that govern cell fate.

biochemistry↗