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Research is the vital expression of humankind’s most important qualities: curiosity and imagination.

Explorers, inventors, pioneers—dedicated researchers on the frontiers of science and the humanities.

Insight, when it comes, changes everything.

Publications

The NOMIS community of researchers and partners is instrumental in driving interdisciplinary collaboration, generating insights and ultimately advancing our understanding of the world. A key component of these efforts is knowledge sharing. Comprising a unique offering of engaging scientific lectures, insightful films about our awardees’ research, and a comprehensive publication database, NOMIS Insights are designed to facilitate the sharing of knowledge. They showcase the groundbreaking findings and innovative perspectives born from NOMIS-supported research endeavors, embodying our dedication to enabling scientific progress.

Our NOMIS Insight database provides a comprehensive source of all publications resulting from NOMIS-supported research projects.

Alzheimer’s disease-associated CD83(+) microglia are linked with increased immunoglobulin G4 and human cytomegalovirus in the gut, vagal nerve, and brain

NOMIS Researcher(s)

Published in

December 19, 2024

INTRODUCTION: While there may be microbial contributions to Alzheimer’s disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+)microglia subtype associated with increased immunoglobulinG4(IgG4) in the transverse colon (TC).

METHODS: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association.

RESULTS: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death.

DISCUSSION: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+)microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+)microglia.

Research field(s)
Genetics & Heredity, Neurology & Neurosurgery, Biology

DOI
10.1002/alz.14401

Biased expectations about future choice options predict sequential economic decisions

NOMIS Researcher(s)

Published in

December 18, 2024

Considerable research has shown that people make biased decisions in “optimal stopping problems”, where options are encountered sequentially, and there is no opportunity to recall rejected options or to know upcoming options in advance (e.g. when flat hunting or choosing a spouse). Here, we used computational modelling to identify the mechanisms that best explain decision bias in the context of an especially realistic version of this problem: the full-information problem. We eliminated a number of factors as potential instigators of bias. Then, we examined sequence length and payoff scheme: two manipulations where an optimality model recommends adjusting the sampling rate. Here, participants were more reluctant to increase their sampling rates when it was optimal to do so, leading to increased undersampling bias. Our comparison of several computational models of bias demonstrates that many participants maintain these relatively low sampling rates because of suboptimally pessimistic expectations about the quality of future options (i.e. a mis-specified prior distribution). These results support a new theory about how humans solve full information problems. Understanding the causes of decision error could enhance how we conduct real world sequential searches for options, for example how online shopping or dating applications present options to users.

Research field(s)
Behavioral Science & Comparative Psychology

DOI
10.1038/s44271-024-00172-8

Synaptic basis of feature selectivity in hippocampal neurons

NOMIS Researcher(s)

Published in

December 18, 2024

A central question in neuroscience is how synaptic plasticity shapes the feature selectivity of neurons in behaving animals1. Hippocampal CA1 pyramidal neurons display one of the most striking forms of feature selectivity by forming spatially and contextually selective receptive fields called place fields, which serve as a model for studying the synaptic basis of learning and memory. Various forms of synaptic plasticity have been proposed as cellular substrates for the emergence of place fields. However, despite decades of work, our understanding of how synaptic plasticity underlies place-field formation and memory encoding remains limited, largely due to a shortage of tools and technical challenges associated with the visualization of synaptic plasticity at the single-neuron resolution in awake behaving animals. To address this, we developed an all-optical approach to monitor the spatiotemporal tuning and synaptic weight changes of dendritic spines before and after the induction of a place field in single CA1 pyramidal neurons during spatial navigation. We identified a temporally asymmetric synaptic plasticity kernel resulting from bidirectional modifications of synaptic weights around the induction of a place field. Our work identified compartment-specific differences in the magnitude and temporal expression of synaptic plasticity between basal dendrites and oblique dendrites. Our results provide experimental evidence linking synaptic plasticity to the rapid emergence of spatial selectivity in hippocampal neurons, a critical prerequisite for episodic memory.

Research field(s)
Neuroscience

DOI
10.1038/s41586-024-08325-9

Spatial transcriptomic clocks reveal cell proximity effects in brain ageing

NOMIS Researcher(s)

Published in

December 18, 2024

Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions—exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell–cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.

Research field(s)
Bioinformatics, Biochemistry & Molecular Biology, Immunology, Neurology & Neurosurgery

DOI
10.1038/s41586-024-08334-8

Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19

NOMIS Researcher(s)

Published in

December 11, 2024

SARS-CoV-2 infection is associated with long-lasting neurological symptoms, although the underlying mechanisms remain unclear. Using optical clearing and imaging, we observed the accumulation of SARS-CoV-2 spike protein in the skull-meninges-brain axis of human COVID-19 patients, persisting long after viral clearance. Further, biomarkers of neurodegeneration were elevated in the cerebrospinal fluid from long COVID patients, and proteomic analysis of human skull, meninges, and brain samples revealed dysregulated inflammatory pathways and neurodegeneration-associated changes. Similar distribution patterns of the spike protein were observed in SARS-CoV-2-infected mice. Injection of spike protein alone was sufficient to induce neuroinflammation, proteome changes in the skull-meninges-brain axis, anxiety-like behavior, and exacerbated outcomes in mouse models of stroke and traumatic brain injury. Vaccination reduced but did not eliminate spike protein accumulation after infection in mice. Our findings suggest persistent spike protein at the brain borders may contribute to lasting neurological sequelae of COVID-19.

Research field(s)
Molecular Biology, Virology, Immunology

DOI
10.1016/j.chom.2024.11.007

Genome editing with the HDR-enhancing DNA-PKcs inhibitor AZD7648 causes large-scale genomic alterations

NOMIS Researcher(s)

Published in

November 27, 2024

The DNA-PKcs inhibitor AZD7648 enhances CRISPR–Cas9-directed homology-directed repair efficiencies, with potential for clinical utility, but its possible on-target consequences are unknown. We found that genome editing with AZD7648 causes frequent kilobase-scale and megabase-scale deletions, chromosome arm loss and translocations. These large-scale chromosomal alterations evade detection through typical genome editing assays, prompting caution in deploying AZD7648 and reinforcing the need to investigate multiple types of potential editing outcomes.

Research field(s)
Biochemistry & Molecular Biology, Genetics & Heredity

DOI
10.1038/s41587-024-02488-6

Archaeal type six secretion system mediates contact-dependent antagonism

NOMIS Researcher(s)

Published in

November 15, 2024

Microbial communities are shaped by cell-cell interactions. Although archaea are often found in associations with other microorganisms, the mechanisms structuring these communities are poorly understood. Here, we report on the structure and function of haloarchaeal contractile injection systems (CISs). Using a combination of functional assays and time-lapse imaging, we show that Halogeometricum borinquense exhibits antagonism toward Haloferax volcanii by inducing cell lysis and inhibiting proliferation. This antagonism is contact-dependent and requires a functional CIS, which is encoded by a gene cluster that is associated with toxin-immunity pairs. Cryo–focused ion beam milling and imaging by cryo–electron tomography revealed that these CISs are bound to the cytoplasmic membrane, resembling the bacterial type six secretion systems (T6SSs). We show that related T6SS gene clusters are conserved and expressed in other haloarchaeal strains, which exhibit antagonistic behavior. Our data provide a mechanistic framework for understanding how archaea may shape microbial communities and affect the food webs they inhabit.

Research field(s)
Microbiology

DOI
10.1126/sciadv.adp7088

Natural processes and natureculture – A relational understanding of nature amongst local stakeholders in Swiss parks

NOMIS Researcher(s)

Published in

November 12, 2024

Various scholars have criticized that formal Western thinking was dichotomous and substantialist, leading to an alienation from nature and to its exploitation in industrialized societies. Critics argue that a relational turn towards a more holistic, process-based and relational approach to address the world would be an important step to overcome these problems. Such a relational turn involves a shift towards more flexible and inclusive concepts. We analyse ‘nature’ concepts of local stakeholders in Swiss nature parks to examine whether they contain any relational elements. Indeed, we found that all stakeholders interviewed see themselves as part of nature. Many reported how they experience nature in active processes and see nature as a collaborator and partner. Moreover, they do not strictly separate between natural and cultural elements in their environment. We conclude that a relational turn in environmental policy in Western countries could build on these relational elements in nature concepts of the local population.

Research field(s)
Philosophy & Theology

DOI
10.1080/26395916.2024.2421306

A leader I can(not) trust: understanding the path from epistemic trust to political leader choices via dogmatism

NOMIS Researcher(s)

Published in

October 31, 2024

There is growing concern about the impact of declining political trust on democracies. Psychological research has introduced the concept of epistemic (mis)trust as a stable disposition acquired through development, which may influence our sociopolitical engagement. Given trust’s prominence in current politics, we examined the relationship between epistemic trust and people’s choices of (un)trustworthy political leaders. In two representative samples in the UK and US (N = 1096), we tested whether epistemic trust predicts political leader choices through three political dimensions: dogmatism, political trust, and ideology. Although epistemic trust did not directly predict choices of political leaders, it predicted dogmatism and political ideology, which in turn predicted choices of political leaders. A network analysis revealed that epistemic trust and political dimensions only interact through their common connection with dogmatism. These findings suggest that cognitive and affective development may underlie an individual’s political ideology and associated beliefs.

Research field(s)
Political Science & Public Administration, Psychology & Cognitive Sciences

DOI
10.1017/pls.2024.11

Mechanism of bacterial predation via ixotrophy

NOMIS Researcher(s)

Published in

October 18, 2024

Ixotrophy is a contact-dependent predatory strategy of filamentous bacteria in aquatic environments for which the molecular mechanism remains unknown. We show that predator-prey contact can be established by gliding motility or extracellular assemblages we call “grappling hooks.” Cryo–electron microscopy identified the grappling hooks as heptamers of a type IX secretion system substrate. After close predator-prey contact is established, cryo–electron tomography and functional assays showed that puncturing by a type VI secretion system mediated killing. Single-cell analyses with stable isotope–labeled prey revealed that prey components are taken up by the attacker. Depending on nutrient availability, insertion sequence elements toggle the activity of ixotrophy. A marine metagenomic time series shows coupled dynamics of ixotrophic bacteria and prey. We found that the mechanism of ixotrophy involves multiple cellular machineries, is conserved, and may shape microbial populations in the environment.

Research field(s)
Microbiology

DOI
10.1126/science.adp0614

The Food Socioscope: A new instrument to better understand transitions towards greater sustainability

NOMIS Researcher(s)

Published in

October 15, 2024

The Food Socioscope project aims to understand the systemic transition towards greater sustainability in the food sector. It has two main components: a participatory data collection with a community directory, and a comprehensive research effort. The first component builds a community of practitioners from various sectors (e.g., companies, NGOs, public authorities) who manage initiatives promoting food sustainability. This community, facilitated by the Food Socioscope Netboard, fosters knowledge exchange by publishing key characteristics of these initiatives online. The second component collects qualitative data through in-depth field interviews, site visits and videos with practitioners, following a rigorously tested protocol. This in-depth data, capturing activities from micro to macro levels, feeds into the research project to improve understanding of systemic change in food sustainability. The research spans the entire food supply chain and examines the supporting infrastructure and organizational setups. By analysing 600 initiatives, worldwide, within their broader contexts, the project aims to identify mechanisms of transition, including barriers and success factors. To collect, process and analyse its vast amount of qualitative data, in multiple languages, the project uses novel protocols, AI models, network analysis, and other quantitative methods. This paper presents the project and preliminary findings regarding regulation, the asymmetry of social contracts and the practitioners’ motivations.

Research field(s)
Sociology, Social Psychology

DOI
10.5281/zenodo.13935390

Synaptic neoteny of human cortical neurons requires species-specific balancing of SRGAP2-SYNGAP1 cross-inhibition

NOMIS Researcher(s)

Published in

October 14, 2024

Human-specific (HS) genes have been implicated in brain evolution, but their impact on human neuron development and diseases remains unclear. Here, we study SRGAP2B/C, two HS gene duplications of the ancestral synaptic gene SRGAP2A, in human cortical pyramidal neurons (CPNs) xenotransplanted in the mouse cortex. Downregulation of SRGAP2B/C in human CPNs led to strongly accelerated synaptic development, indicating their requirement for the neoteny that distinguishes human synaptogenesis. SRGAP2B/C genes promoted neoteny by reducing the synaptic levels of SRGAP2A,thereby increasing the postsynaptic accumulation of the SYNGAP1 protein, encoded by a major intellectual disability/autism spectrum disorder (ID/ASD) gene. Combinatorial loss-of-function experiments in vivo revealed that the tempo of synaptogenesis is set by the reciprocal antagonism between SRGAP2A and SYNGAP1, which in human CPNs is tipped toward neoteny by SRGAP2B/C. Thus, HS genes can modify the phenotypic expression of genetic mutations leading to ID/ASD through the regulation of human synaptic neoteny.

Research field(s)
Genetics & Heredity

DOI
10.1016/j.neuron.2024.08.021

If you please, draw me a neuron — linking evolutionary tinkering with human neuron evolution

NOMIS Researcher(s)

Published in

October 1, 2024

Animal speciation often involves novel behavioral features that rely on nervous system evolution. Human-specific brain features have been proposed to underlie specialized cognitive functions and to be linked, at least in part, to the evolution of synapses, neurons, and circuits of the cerebral cortex. Here, we review recent results showing that, while the human cortex is composed of a repertoire of cells that appears to be largely similar to the one found in other mammals, human cortical neurons do display specialized features at many levels, from gene expression to intrinsic physiological properties. The molecular mechanisms underlying human species-specific neuronal features remain largely unknown but implicate hominid-specific gene duplicates that encode novel molecular modifiers of neuronal function. The identification of human-specific genetic modifiers of neuronal function brings novel insights on brain evolution and function and, could also provide new insights on human species-specific vulnerabilities to brain disorders.

Research field(s)
Genetics & Heredity, Evolutionary Biology

DOI
10.1016/j.gde.2024.102260

Gradients of Deposition and In Situ Production Drive Global Glacier Organic Matter Composition

NOMIS Researcher(s)

Published in

September 19, 2024

Runoff from rapidly melting mountain glaciers is a dominant source of riverine organic carbon in many high-latitude and high-elevation regions. Glacier dissolved organic carbon is highly bioavailable, and its composition likely reflects internal (e.g., autotrophic production) and external (i.e., atmospheric deposition) sources. However, the balance of these sources across Earth’s glaciers is poorly understood, despite implications for the mineralization and assimilation of glacier organic carbon within recipient ecosystems. We assessed the molecular-level composition of dissolved organic matter from 136 mountain glacier outflows from 11 regions covering six continents using ultrahigh resolution 21 T mass spectrometry. We found substantial diversity in organic matter composition with coherent and predictable (80% accuracy) regional patterns. Employing stable and radiocarbon isotopic analyses, we demonstrate that these patterns are inherently linked to atmospheric deposition and in situ production. In remote regions like Greenland and New Zealand, the glacier organic matter pool appears to be dominated by in situ production. However, downwind of industrial centers (e.g., Alaska and Nepal), fossil fuel combustion byproducts likely underpin organic matter composition, resulting in older and more aromatic material being exported downstream. These findings highlight that the glacier carbon cycle is spatially distinct, with ramifications for predicting the dynamics and fate of glacier organic carbon concurrent with continued retreat and anthropogenic perturbation.

Research field(s)
Conservation Biology, Biology

DOI
10.1029/2024GB008212

Digital solutions in paediatric sepsis: current state, challenges, and opportunities to improve care around the world

NOMIS Researcher(s)

Published in

September 1, 2024
The digitisation of health care is offering the promise of transforming the management of paediatric sepsis, which is a major source of morbidity and mortality in children worldwide. Digital technology is already making an impact in paediatric sepsis, but is almost exclusively benefiting patients in high-resource health-care settings. However, digital tools can be highly scalable and cost-effective, and—with the right planning—have the potential to reduce global health disparities. Novel digital solutions, from wearable devices and mobile apps, to electronic health record-embedded decision support tools, have an unprecedented opportunity to transform paediatric sepsis research and care. In this Series paper, we describe the current state of digital solutions in paediatric sepsis around the world, the advances in digital technology that are enabling the development of novel applications, and the potential effect of advances in artificial intelligence in paediatric sepsis research and clinical care.

Research field(s)
Pediatrics

DOI
10.1016/S2589-7500(24)00141-9

Quality improvement programmes in paediatric sepsis from a global perspective

NOMIS Researcher(s)

Published in

September 1, 2024

Sepsis is a major contributor to poor child health outcomes around the world. The high morbidity, mortality, and societal cost associated with paediatric sepsis render it a global health priority, as summarised in Paper 1 of this Series. Sepsis is characterised by a dysregulated host response to infection that manifests as organ failure, and children are uniquely susceptible to sepsis, as discussed in Paper 2. The focus of this third Series paper is quality improvement in paediatric sepsis. The 2017 WHO resolution on sepsis outlined key aims to reduce the burden of sepsis. As of 2024, only a small number of countries have implemented systematic, paediatric-focused quality improvement programmes to raise sepsis awareness, enhance recognition of sepsis, promote timely treatment, and provide long-term support for paediatric sepsis survivors. We examine programme successes and systematic barriers to quality improvement targeting paediatric sepsis. We highlight the need for programme design to consider the entire patient journey, starting with prevention, caregiver awareness, recognition at home, education of the health-care workforce, development of health-care systems, and establishment of long-term family and survivor support extending beyond the intensive care unit. Building on lessons learnt from existing quality improvement programmes, we outline implementation strategies and measures to enable benchmarking. Ultimately, quality improvement on a global scale can only be accelerated through a global learning platform focusing on paediatric sepsis.

This is the third in a Series of four papers on paediatric sepsis (Paper 4 appears in The Lancet Digital Health). All papers in the Series are available at thelancet.com/series/paediatric-sepsis

Research field(s)
Pediatrics

DOI
10.1016/S2352-4642(24)00142-1

Susceptibility to childhood sepsis, contemporary management, and future directions

NOMIS Researcher(s)

Published in

September 1, 2024

Sepsis disproportionally affects children across all health-care settings and is one of the leading causes of morbidity and mortality in neonatal and paediatric age groups. As shown in the first paper in this Series, the age-specific incidence of sepsis is highest during the first years of life, before approaching adult incidence rates during adolescence. In the second paper in this Series, we focus on the unique susceptibility of paediatric patients to sepsis and how the underlying dysregulated host response relates to developmental aspects of children’s immune system, genetic, perinatal, and environmental factors, and comorbidities and socioeconomic determinants of health, which often differ between children and adults. State-of-the-art clinical management of paediatric sepsis is organised around three treatment pillars—diagnosis, early resuscitation, and titration of advanced care—and we examine available treatment guidelines and the limitations of their supporting evidence. Serious evidence gaps remain in key areas of paediatric sepsis care, especially surrounding recognition, common interventions, and survivor support, and to this end we offer a research roadmap for the next decade that could accelerate targeted diagnostics and personalised use of immunomodulation. However, improving outcomes for children with sepsis relies fundamentally on systematic quality improvement in both recognition and treatment, which is the theme of the third paper in this Series. Digital health, as shown in the fourth and final paper of this Series, holds promising potential in breaking down the barriers that hinder progress in paediatric sepsis care and, ultimately, global child health.

This is the second in a Series of four papers on paediatric sepsis (Paper 4 appears in The Lancet Digital Health). All papers in the Series are available at thelancet.com/series/paediatric-sepsis

Research field(s)
Pediatrics

DOI
10.1016/S2352-4642(24)00141-X

The burden and contemporary epidemiology of sepsis in children

NOMIS Researcher(s)

Published in

September 1, 2024

Sepsis is a dysregulated host response to infection that leads to life-threatening organ dysfunction. Half of the 50 million people affected by sepsis globally every year are neonates and children younger than 19 years. This burden on the paediatric population translates into a disproportionate impact on global child health in terms of years of life lost, morbidity, and lost opportunities for children to reach their developmental potential. This Series on paediatric sepsis presents the current state of diagnosis and treatment of sepsis in children, and maps the challenges in alleviating the burden on children, their families, and society. Drawing on diverse experience and multidisciplinary expertise, we offer a roadmap to improving outcomes for children with sepsis. This first paper of the Series is a narrative review of the burden of paediatric sepsis from low-income to high-income settings. Advances towards improved operationalisation of paediatric sepsis across all age groups have facilitated more standardised assessment of the Global Burden of Disease estimates of the impact of sepsis on child health, and these estimates are expected to gain further precision with the roll out of the new Phoenix criteria for sepsis. Sepsis remains one of the leading causes of childhood morbidity and mortality, with immense direct and indirect societal costs. Although substantial regional differences persist in relation to incidence, microbiological epidemiology, and outcomes, these cannot be explained by differences in income level alone. Recent insights into post-discharge sequelae after paediatric sepsis, ranging from late mortality and persistent neurodevelopmental impairment to reduced health-related quality of life, show how common post-sepsis syndrome is in children. Targeting sepsis as a key contributor to poor health outcomes in children is therefore an essential component of efforts to meet the Sustainable Development Goals.

This is the first in a Series of four papers on paediatric sepsis (Paper 4 appears in The Lancet Digital Health). All papers in the Series are available at thelancet.com/series/paediatric-sepsis

Research field(s)
Pediatrics

DOI
10.1016/S2352-4642(24)00140-8

Docking a flexible basket onto the core of the nuclear pore complex

NOMIS Researcher(s)

Published in

August 13, 2024

The nuclear basket attaches to the nucleoplasmic side of the nuclear pore complex (NPC), coupling transcription to mRNA quality control and export. The basket expands the functional repertoire of a subset of NPCs in Saccharomyces cerevisiae by drawing a unique RNA/protein interactome. Yet, how the basket docks onto the NPC core remains unknown. By integrating AlphaFold-based interaction screens, electron microscopy and membrane-templated reconstitution, we uncovered a membrane-anchored tripartite junction between basket and NPC core. The basket subunit Nup60 harbours three adjacent short linear motifs, which connect Mlp1, a parallel homodimer consisting of coiled-coil segments interrupted by flexible hinges, and the Nup85 subunit of the Y-complex. We reconstituted the Y-complex•Nup60•Mlp1 assembly on a synthetic membrane and validated the protein interfaces in vivo. Here we explain how a short linear motif-based protein junction can substantially reshape NPC structure and function, advancing our understanding of compositional and conformational NPC heterogeneity.

Research field(s)
Biochemistry & Molecular Biology, Biology

DOI
10.1038/s41556-024-01484-x

Removal of TREX1 activity enhances CRISPR–Cas9-mediated homologous recombination

NOMIS Researcher(s)

Published in

August 12, 2024

CRISPR–Cas9-mediated homology-directed repair (HDR) can introduce desired mutations at targeted genomic sites, but achieving high efficiencies is a major hurdle in many cell types, including cells deficient in DNA repair activity. In this study, we used genome-wide screening in Fanconi anemia patient lymphoblastic cell lines to uncover suppressors of CRISPR–Cas9-mediated HDR. We found that a single exonuclease, TREX1, reduces HDR efficiency when the repair template is a single-stranded or linearized double-stranded DNA. TREX1 expression serves as a biomarker for CRISPR–Cas9-mediated HDR in that the high TREX1 expression present in many different cell types (such as U2OS, Jurkat, MDA-MB-231 and primary T cells as well as hematopoietic stem and progenitor cells) predicts poor HDR. Here we demonstrate rescue of HDR efficiency (ranging from two-fold to eight-fold improvement) either by TREX1 knockout or by the use of single-stranded DNA templates chemically protected from TREX1 activity. Our data explain why some cell types are easier to edit than others and indicate routes for increasing CRISPR–Cas9-mediated HDR in TREX1-expressing contexts.

Research field(s)
Biochemistry & Molecular Biology, Genetics & Heredity

DOI
10.1038/s41587-024-02356-3

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