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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.

Surpassing the Resistance Quantum with a Geometric Superinductor

NOMIS Researcher(s)

Published in

October 29, 2020

Superinductors have a characteristic impedance exceeding the resistance quantum RQ≈6.45kω, which leads to a suppression of ground-state charge fluctuations. Applications include the realization of hardware-protected qubits for fault-tolerant quantum computing, improved coupling to small-dipole-moment objects, and the definition of a new quantum-metrology standard for the ampere. In this work, we refute the widespread notion that superinductors can only be implemented based on kinetic inductance, i.e., using disordered superconductors or Josephson-junction arrays. We present the modeling, fabrication, and characterization of 104 planar aluminum-coil resonators with a characteristic impedance up to 30.9 kω at 5.6 GHz and a capacitance down to ≤1 fF, with low loss and a power handling reaching 108 intracavity photons. Geometric superinductors are free of uncontrolled tunneling events and offer high reproducibility, linearity, and the ability to couple magnetically – properties that significantly broaden the scope of future quantum circuits.

Research field(s)
Natural Sciences, Physics & Astronomy, Applied Physics

DOI
10.1103/PhysRevApplied.14.044055

Optimised biomolecular extraction for metagenomic analysis of microbial biofilms from high-mountain streams

NOMIS Researcher(s)

Published in

October 27, 2020

Glacier-fed streams (GFS) are harsh ecosystems dominated by microbial life organized in benthic biofilms, yet the biodiversity and ecosystem functions provided by these communities remain under-appreciated. To better understand the microbial processes and communities contributing to GFS ecosystems, it is necessary to leverage high throughput sequencing. Low biomass and high inorganic particle load in GFS sediment samples may affect nucleic acid extraction efficiency using extraction methods tailored to other extreme environments such as deep-sea sediments. Here, we benchmarked the utility and efficacy of four extraction protocols, including an up-scaled phenolchloroform protocol. We found that established protocols for comparable sample types consistently failed to yield sufficient high-quality DNA, delineating the extreme character of GFS. The methods differed in the success of downstream applications such as library preparation and sequencing. An adapted phenol-chloroform-based extraction method resulted in higher yields and better recovered the expected taxonomic profile and abundance of reconstructed genomes when compared to commercially-available methods. Affordable and straight-forward, this method consistently recapitulated the abundance and genomes of a mock community, including eukaryotes. Moreover, by increasing the amount of input sediment, the protocol is readily adjustable to the microbial load of the processed samples without compromising protocol efficiency. Our study provides a first systematic and extensive analysis of the different options for extraction of nucleic acids from glacier-fed streams for high-throughput sequencing applications, which may be applied to other extreme environments.

Research field(s)
Natural Sciences, Biology, Ecology

DOI
10.7717/peerj.9973

Genomic and epigenomic landscaping defines new therapeutic targets for adenosquamous carcinoma of the pancreas

NOMIS Researcher(s)

Published in

October 15, 2020

Adenosquamous cancer of the pancreas (ASCP) is a subtype of pancreatic cancer that has a worse prognosis and greater metastatic potential than the more common pancreatic ductal adenocarcinoma (PDAC) subtype. To distinguish the genomic landscape of ASCP and identify actionable targets for this lethal cancer, we applied DNA content flow cytometry to a series of 15 tumor samples including five patient-derived xenografts (PDX). We interrogated purified sorted tumor fractions from these samples with whole-genome copy-number variant (CNV), whole-exome sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analyses. These identified a variety of somatic genomic lesions targeting chromatin regulators in ASCP genomes that were superimposed on well-characterized genomic lesions including mutations in TP53 (87%) and KRAS (73%), amplification of MYC (47%), and homozygous deletion of CDKN2A (40%) that are common in PDACs. Furthermore, a comparison of ATAC-seq profiles of three ASCP and three PDAC genomes using flow-sorted PDX models identified genes with accessible chromatin unique to the ASCP genomes, including the lysine methyltransferase SMYD2 and the pancreatic cancer stem cell regulator RORC in all three ASCPs, and a FGFR1-ERLIN2 fusion associated with focal CNVs in both genes in a single ASCP. Finally, we demonstrate significant activity of a pan FGFR inhibitor against organoids derived from the FGFR1-ERLIN2 fusion-positive ASCP PDX model. Our results suggest that the genomic and epigenomic landscape of ASCP provide new strategies for targeting this aggressive subtype of pancreatic cancer.

Research field(s)
Health Sciences, Clinical Medicine, Oncology & Carcinogenesis

DOI
10.1158/0008-5472.CAN-20-0078

Mutational selection in normal urothelium

NOMIS Researcher(s)

Published in

October 2, 2020

null

Research field(s)
Health Sciences, Clinical Medicine, Oncology & Carcinogenesis

DOI
10.1126/science.abe0955

Shifts and drifts in prion science

NOMIS Researcher(s)

Published in

October 2, 2020

null

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1126/science.abb8577

Deep posteromedial cortical rhythm in dissociation

NOMIS Researcher(s)

Published in

October 1, 2020

Advanced imaging methods now allow cell-type-specific recording of neural activity across the mammalian brain, potentially enabling the exploration of how brain-wide dynamical patterns give rise to complex behavioural states1–12. Dissociation is an altered behavioural state in which the integrity of experience is disrupted, resulting in reproducible cognitive phenomena including the dissociation of stimulus detection from stimulus-related affective responses. Dissociation can occur as a result of trauma, epilepsy or dissociative drug use13,14, but despite its substantial basic and clinical importance, the underlying neurophysiology of this state is unknown. Here we establish such a dissociation-like state in mice, induced by precisely-dosed administration of ketamine or phencyclidine. Large-scale imaging of neural activity revealed that these dissociative agents elicited a 1–3-Hz rhythm in layer 5 neurons of the retrosplenial cortex. Electrophysiological recording with four simultaneously deployed high-density probes revealed rhythmic coupling of the retrosplenial cortex with anatomically connected components of thalamus circuitry, but uncoupling from most other brain regions was observed—including a notable inverse correlation with frontally projecting thalamic nuclei. In testing for causal significance, we found that rhythmic optogenetic activation of retrosplenial cortex layer 5 neurons recapitulated dissociation-like behavioural effects. Local retrosplenial hyperpolarization-activated cyclic-nucleotide-gated potassium channel 1 (HCN1) pacemakers were required for systemic ketamine to induce this rhythm and to elicit dissociation-like behavioural effects. In a patient with focal epilepsy, simultaneous intracranial stereoencephalography recordings from across the brain revealed a similarly localized rhythm in the homologous deep posteromedial cortex that was temporally correlated with pre-seizure self-reported dissociation, and local brief electrical stimulation of this region elicited dissociative experiences. These results identify the molecular, cellular and physiological properties of a conserved deep posteromedial cortical rhythm that underlies states of dissociation.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1038/s41586-020-2731-9

Network Engineering Using Autonomous Agents Increases Cooperation in Human Groups

NOMIS Researcher(s)

Published in

September 25, 2020

Cooperation in human groups is challenging, and various mechanisms are required to sustain it, although it nevertheless usually decays over time. Here, we perform theoretically informed experiments involving networks of humans (1,024 subjects in 64 networks) playing a public-goods game to which we sometimes added autonomous agents (bots) programmed to use only local knowledge. We show that cooperation can not only be stabilized, but even promoted, when the bots intervene in the partner selections made by the humans, re-shaping social connections locally within a larger group. Cooperation rates increased from 60.4% at baseline to 79.4% at the end. This network-intervention strategy outperformed other strategies, such as adding bots playing tit-for-tat. We also confirm that even a single bot can foster cooperation in human groups by using a mixed strategy designed to support the development of cooperative clusters. Simple artificial intelligence can increase the cooperation of groups.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.isci.2020.101438

Microwave quantum illumination with a digital phase-conjugated receiver

NOMIS Researcher(s)

Published in

September 21, 2020

Quantum illumination is a sensing technique that employs entangled signal-idler beams to improve the detection efficiency of low-reflectivity objects in environments with large thermal noise. The advantage over classical strategies is evident at low signal brightness, a feature which could make the protocol an ideal prototype for non-invasive scanning or low-power short-range radar. Here we experimentally investigate the concept of quantum illumination at microwave frequencies, by generating entangled fields using a Josephson parametric converter which are then amplified to illuminate a room-temperature object at a distance of 1 meter. Starting from experimental data, we simulate the case of perfect idler photon number detection, which results in a quantum advantage compared to the relative classical benchmark. Our results highlight the opportunities and challenges on the way towards a first room-temperature application of microwave quantum circuits.

Research field(s)
Applied Sciences, Information & Communication Technologies, Networking & Telecommunications

DOI
10.1109/RadarConf2043947.2020.9266397

Associative memory and in vivo brain pathology in asymptomatic presenilin-1 E280A carriers

NOMIS Researcher(s)

Published in

September 8, 2020

Objective: To determine whether performance on the Free and Cued Selective Reminding Test (FCSRT) is associated with PET in vivo markers of brain pathology and whether it can distinguish those who will develop dementia later in life due to autosomal-dominant Alzheimer disease (AD) from age-matched controls. Methods:Twenty-four cognitively unimpaired Presenilin-1 E280A carriers (mean age 36 years) and 28 noncarriers (mean age 37 years) underwent Pittsburg compound B-PET (amyloid), flortaucipir-PET (tau), and cognitive testing, including the FCSRT (immediate and delayed free and cued recall scores). Linear regressions were used to examine the relationships among FCSRT scores, age, mean cortical amyloid, and regional tau burden. Results:Free and total recall scores did not differ between cognitively unimpaired mutation carriers and noncarriers. Greater age predicted lower free recall and delayed free and total recall scores in carriers. In cognitively impaired carriers, delayed free recall predicted greater amyloid burden and entorhinal tau, while worse immediate free recall scores predicted greater tau in the inferior temporal and entorhinal cortices. In turn, in all carriers, lower free and total recall scores predicted greater amyloid and regional tau pathology. Conclusions:FCSRT scores were associated with in vivo markers of AD-related pathology in cognitively unimpaired individuals genetically determined to develop dementia. Difficulties on free recall, particularly delayed recall, were evident earlier in the disease trajectory, while difficulties on cued recall were seen only as carriers neared the onset of dementia, consistent with the pathologic progression of the disease. Findings suggest that the FCSRT can be a useful measure to track disease progression in AD.

Research field(s)
Health Sciences, Clinical Medicine, Neurology & Neurosurgery

DOI
10.1212/WNL.0000000000010177

A Neanderthal Sodium Channel Increases Pain Sensitivity in Present-Day Humans

NOMIS Researcher(s)

Published in

September 7, 2020

The sodium channel Nav1.7 is crucial for impulse generation and conduction in peripheral pain pathways [1]. In Neanderthals, the Nav1.7 protein carried three amino acid substitutions (M932L, V991L, and D1908G) relative to modern humans. We expressed Nav1.7 proteins carrying all combinations of these substitutions and studied their electrophysiological effects. Whereas the single amino acid substitutions do not affect the function of the ion channel, the full Neanderthal variant carrying all three substitutions, as well as the combination of V991L with D1908G, shows reduced inactivation, suggesting that peripheral nerves were more sensitive to painful stimuli in Neanderthals than in modern humans. We show that, due to gene flow from Neanderthals, the three Neanderthal substitutions are found in ∼0.4% of present-day Britons, where they are associated with heightened pain sensitivity.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.cub.2020.06.045

Protective anti-prion antibodies in human immunoglobulin repertoires

NOMIS Researcher(s)

Published in

September 7, 2020

Prion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here, we identified > 6,000 PrP-binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage-derived antibodies. When expressed recombinantly, these antibodies exhibited anti-PrP reactivity. Furthermore, we surveyed 48,718 samples from 37,894 hospital patients for the presence of anti-PrP IgGs and found 21 high-titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti-PrP autoimmunity is innocuous. The existence of anti-prion antibodies in unbiased human immunological repertoires suggests that they might clear nascent prions early in life. Combined with the reported lack of such antibodies in carriers of disease-associated PRNP mutations, this suggests a link to the low incidence of spontaneous prion diseases in human populations.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.15252/emmm.202012739

Genome wide analysis points towards subtype-specific diseases in different genetic forms of amyotrophic lateral sclerosis

NOMIS Researcher(s)

Published in

September 2, 2020

Amyotropic lateral sclerosis (ALS) is a lethally progressive and irreversible neurodegenerative disease marked by apparent death of motor neurons present in the spinal cord, brain stem and motor cortex. While more and more gene mutants being established for genetic ALS, the vast majority suffer from sporadic ALS (>90%). It has been challenging, thus, to model sporadic ALS which is one reason why the underlying pathophysiology remains elusive and has stalled the development of therapeutic strategies of this progressive motor neuron disease. To further unravel these pathological signaling pathways, human induced pluripotent stem cell (hiPSCs)-derived motor neurons (MNs) from FUS-and SOD1 ALS patients and healthy controls were systematically compared to independent published datasets. Here through this study we created a gene profile of ALS by analyzing the DEGs, the Kyoto encyclopedia of Genes and Genomes (KEGG) pathways, the interactome and the transcription factor profiles (TF) that would identify altered molecular/functional signatures and their interactions at both transcriptional (mRNAs) and translational levels (hub proteins and TFs). Our findings suggest that FUS and SOD1 may develop from dysregulation in several unique pathways and herpes simplex virus (HSV) infection was among the topmost predominant cellular pathways connected to FUS and not to SOD1. In contrast, SOD1 is mainly characterized by alterations in the metabolic pathways and alterations in the neuroactive-ligand–receptor interactions. This suggests that different genetic ALS forms are singular diseases rather than part of a common spectrum. This is important for patient stratification clearly pointing towards the need for individualized medicine approaches in ALS.

Research field(s)
Natural Sciences, Physics & Astronomy, Chemical Physics

DOI
10.3390/ijms21186938

Direct reprogramming of human smooth muscle and vascular endothelial cells reveals defects associated with aging and hutchinson-gilford progeria syndrome

NOMIS Researcher(s)

Published in

September 1, 2020

Vascular dysfunctions are a common feature of multiple age-related diseases. However, modeling healthy and pathological aging of the human vasculature represents an unresolved experimental challenge. Here, we generated induced vascular endothelial cells (iVECs) and smooth muscle cells (iSMCs) by direct reprogramming of healthy human fibroblasts from donors of different ages and Hutchinson-Gilford Progeria Syndrome (HGPS) patients. iVECs induced from old donors revealed upregulation of GSTM1 and PALD1, genes linked to oxidative stress, inflammation and endothelial junction stability, as vascular aging markers. A functional assay performed on PALD1 KD VECs demonstrated a recovery in vascular permeability. We found that iSMCs from HGPS donors overexpressed bone morphogenetic protein (BMP) 4, which plays a key role in both vascular calcification and endothelial barrier damage observed in HGPS. Strikingly, BMP4 concentrations are higher in serum from HGPS vs. age-matched mice. Furthermore, targeting BMP4 with blocking antibody recovered the functionality of the vascular barrier in vitro, hence representing a potential future therapeutic strategy to limit cardiovascular dysfunction in HGPS. These results show that iVECs and iSMCs retain disease-related signatures, allowing modeling of vascular aging and HGPS in vitro.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.7554/ELIFE.54383

Controlled Cycling and Quiescence Enables Efficient HDR in Engraftment-Enriched Adult Hematopoietic Stem and Progenitor Cells

NOMIS Researcher(s)

Published in

September 1, 2020

Genome editing often takes the form of either error-prone sequence disruption by non-homologous end joining (NHEJ) or sequence replacement by homology-directed repair (HDR). Although NHEJ is generally effective, HDR is often difficult in primary cells. Here, we use a combination of immunophenotyping, next-generation sequencing, and single-cell RNA sequencing to investigate and reprogram genome editing outcomes in subpopulations of adult hematopoietic stem and progenitor cells. We find that although quiescent stem-enriched cells mostly use NHEJ, non-quiescent cells with the same immunophenotype use both NHEJ and HDR. Inducing quiescence before editing results in a loss of HDR in all cell subtypes. We develop a strategy of controlled cycling and quiescence that yields a 6-fold increase in the HDR/NHEJ ratio in quiescent stem cells ex vivo and in vivo. Our results highlight the tension between editing and cellular physiology and suggest strategies to manipulate quiescent cells for research and therapeutic genome editing. Shin et al. find that quiescent blood stem cells only perform error-prone NHEJ to repair double-strand breaks, whereas cycling blood stem cells perform both error-prone NHEJ and precise HDR. They show that inducing quiescence after a short period of cycling yields blood stem cells harboring high levels of HDR.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.celrep.2020.108093

Ribosomal profiling during prion disease uncovers progressive translational derangement in glia but not in neurons

NOMIS Researcher(s)

Published in

September 1, 2020

Prion diseases are caused by PrPSc, a self-replicating pathologically misfolded protein that exerts toxicity predominantly in the brain. The administration of PrPSc causes a robust, reproducible and specific disease manifestation. Here, we have applied a combination of translating ribosome affinity purification and ribosome profiling to identify biologically relevant prion-induced changes during disease progression in a cell-type-specific and genome-wide manner. Terminally diseased mice with severe neurological symptoms showed extensive alterations in astrocytes and microglia. Surprisingly, we detected only minor changes in the translational profiles of neurons. Prion-induced alterations in glia overlapped with those identified in other neurodegenerative diseases, suggesting that similar events occur in a broad spectrum of pathologies. Our results suggest that aberrant translation within glia may suffice to cause severe neurological symptoms and may even be the primary driver of prion disease.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.7554/ELIFE.62911

Bio-synthesized iron oxide nanoparticles for cancer treatment

NOMIS Researcher(s)

Published in

August 30, 2020

Various living organisms, such as bacteria, plants, and animals can synthesize iron oxide nanoparticles (IONP). The mechanism of nanoparticle (NP) formation is usually described as relying on the reduction of ferric/ferrous iron ions into crystallized nanoparticulate iron that is surrounded by an organic stabilizing layer. The properties of these NP are characterized by a composition made of different types of iron oxide whose most stable and purest one appears to be maghemite, by a size predominantly comprised between 5 and 380 nm, by a crystalline core, by a surface charge which depends on the nature of the material coating the iron oxide, and by certain other properties such as a sterility, stability, production in mass, absence of aggregation, that have apparently only been studied in details for IONP synthesized by magnetotactic bacteria, called magnetosomes. In the majority of studies, bio-synthesized IONP are described as being biocompatible and as not inducing cytotoxicity towards healthy cells. Anti-tumor activity of bio-synthesized IONP has mainly been demonstrated in vitro, where this type of NP displayed cytotoxicity towards certain tumor cells, e.g. through the anti-tumor activity of IONP coating or through IONP anti-oxidizing property. Concerning in vivo anti-tumor activity, it was essentially highlighted for magnetosomes administered in different types of glioblastoma tumors (U87-Luc and GL-261), which were exposed to a series of alternating magnetic field applications, resulting in mild hyperthermia treatments at typical temperatures of 41–45 °C, leading to the full disappearance of these tumors without any observable side effects.

Research field(s)
Health Sciences, Clinical Medicine, Pharmacology & Pharmacy

DOI
10.1016/j.ijpharm.2020.119472

Architecture and function of human uromodulin filaments in urinary tract infections

NOMIS Researcher(s)

Published in

August 21, 2020

Uromodulin is the most abundant protein in human urine, and it forms filaments that antagonize the adhesion of uropathogens; however, the filament structure and mechanism of protection remain poorly understood. We used cryo–electron tomography to show that the uromodulin filament consists of a zigzag-shaped backbone with laterally protruding arms. N-glycosylation mapping and biophysical assays revealed that uromodulin acts as a multivalent ligand for the bacterial type 1 pilus adhesin, presenting specific epitopes on the regularly spaced arms. Imaging of uromodulin-uropathogen interactions in vitro and in patient urine showed that uromodulin filaments associate with uropathogens and mediate bacterial aggregation, which likely prevents adhesion and allows clearance by micturition. These results provide a framework for understanding uromodulin in urinary tract infections and in its more enigmatic roles in physiology and disease.

Research field(s)
Health Sciences, Biomedical Research, Biochemistry & Molecular Biology

DOI
10.1126/science.aaz9866

Are the Two Approaches to Moral Economy Irreconcilable?

NOMIS Researcher(s)

Published in

August 7, 2020

The concept of moral economy stems from two theoretical traditions: that of E. P. Thompson, which corresponds to the norms and obligations involved in traditional economies, and has nourished the works of social historians and political anthropologists; and that of Lorraine Daston, which characterizes the values and affects regulating the activity of a given group in a given time, and has inspired historians and anthropologists of science. This essay offers a third reading attempting to reconnect these irreconcilable approaches by considering a moral economy as the production, circulation, appropriation, and confrontation of values and affects with regard to a significant social object, such as immigration or punishment, rather than to a social group. This new approach allows us to address some of the issues raised by R. H. Tawney’s analysis of religion and by Marcel Mauss’s interpretation of the gift. Particular examples are drawn from the capitalist devaluation of human lives and the humanitarian asymmetrical relation of obligation.

Research field(s)
Social Sciences

DOI
10.1353/hum.2020.0010

100 Opportunities for More Inclusive Ocean Research: Cross-Disciplinary Research Questions for Sustainable Ocean Governance and Management

NOMIS Researcher(s)

Published in

August 6, 2020

In order to inform decision making and policy, research to address sustainability challenges requires cross-disciplinary approaches that are co-created with a wide and inclusive diversity of disciplines and stakeholders. As the UN Decade of Ocean Science for Sustainable Development approaches, it is therefore timely to take stock of the global range of cross-disciplinary questions to inform the development of policies to restore and sustain ocean health. We synthesized questions from major science and policy horizon scanning exercises, identifying 89 questions with relevance for ocean policy and governance. We then scanned the broad ocean science literature to examine issues potentially missed in the horizon scans and supplemented the horizon scan outcome with 11 additional questions. This resulted in an unprioritized list of 100 general questions that would require a cross-disciplinary approach to inform policy. The questions fell into broad categories including: coastal and marine environmental change, managing ocean activities, governance for sustainable oceans, ocean value, and technological and socio-economic innovation. Each question can be customized by ecosystem, region, scale, and socio-political context, and is intended to inspire discussions of salient cross-disciplinary research directions to direct scientific research that will inform policies. Governance and management responses to these questions will best be informed by drawing upon a diversity of natural and social sciences, local and traditional knowledge, and engagement of different sectors and stakeholders.

Research field(s)
Natural Sciences, Biology, Marine Biology & Hydrobiology

DOI
10.3389/fmars.2020.00576

ATF4 Regulates MYB to Increase γ-Globin in Response to Loss of β-Globin

NOMIS Researcher(s)

Published in

August 4, 2020

β-Hemoglobinopathies can trigger rapid production of red blood cells in a process known as stress erythropoiesis. Cellular stress prompts differentiating erythroid precursors to express high levels of fetal γ-globin. However, the mechanisms underlying γ-globin production during cellular stress are still poorly defined. Here, we use CRISPR-Cas genome editing to model the stress caused by reduced levels of adult β-globin. We find that decreased β-globin is sufficient to induce robust re-expression of γ-globin, and RNA sequencing (RNA-seq) of differentiating isogenic erythroid precursors implicates ATF4 as a causal regulator of this response. ATF4 binds within the HBS1L-MYB intergenic enhancer and regulates expression of MYB, a known γ-globin regulator. Overall, the reduction of ATF4 upon β-globin knockout decreases the levels of MYB and BCL11A. Identification of ATF4 as a key regulator of globin compensation adds mechanistic insight to the poorly understood phenomenon of stress-induced globin compensation and could inform strategies to treat hemoglobinopathies.

Research field(s)
Health Sciences, Biomedical Research, Developmental Biology

DOI
10.1016/j.celrep.2020.107993

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