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Publications in Health Sciences by NOMIS researchers

Dysregulation of BRD4 Function Underlies the Functional Abnormalities of MeCP2 Mutant Neurons

NOMIS Researcher(s)

Published in

July 2, 2020

Rett syndrome (RTT), mainly caused by mutations in methyl-CpG binding protein 2 (MeCP2), is one of the most prevalent intellectual disorders without effective therapies. Here, we used 2D and 3D human brain cultures to investigate MeCP2 function. We found that MeCP2 mutations cause severe abnormalities in human interneurons (INs). Surprisingly, treatment with a BET inhibitor, JQ1, rescued the molecular and functional phenotypes of MeCP2 mutant INs. We uncovered that abnormal increases in chromatin binding of BRD4 and enhancer-promoter interactions underlie the abnormal transcription in MeCP2 mutant INs, which were recovered to normal levels by JQ1. We revealed cell-type-specific transcriptome impairment in MeCP2 mutant region-specific human brain organoids that were rescued by JQ1. Finally, JQ1 ameliorated RTT-like phenotypes in mice. These data demonstrate that BRD4 dysregulation is a critical driver for RTT etiology and suggest that targeting BRD4 could be a potential therapeutic opportunity for RTT.

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

DOI
10.1016/j.molcel.2020.05.016

A metabolic handbook for the COVID-19 pandemic

NOMIS Researcher(s)

Published in

July 1, 2020

For infectious-disease outbreaks, clinical solutions typically focus on efficient pathogen destruction. However, the COVID-19 pandemic provides a reminder that infectious diseases are complex, multisystem conditions, and a holistic understanding will be necessary to maximize survival. For COVID-19 and all other infectious diseases, metabolic processes are intimately connected to the mechanisms of disease pathogenesis and the resulting pathology and pathophysiology, as well as the host defence response to the infection. Here, I examine the relationship between metabolism and COVID-19. I discuss why preexisting metabolic abnormalities, such as type 2 diabetes and hypertension, may be important risk factors for severe and critical cases of infection, highlighting parallels between the pathophysiology of these metabolic abnormalities and the disease course of COVID-19. I also discuss how metabolism at the cellular, tissue and organ levels might be harnessed to promote defence against the infection, with a focus on disease-tolerance mechanisms, and speculate on the long-term metabolic consequences for survivors of COVID-19.

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

DOI
10.1038/s42255-020-0237-2

Dynamic regulation of histone modifications and long-range chromosomal interactions during postmitotic transcriptional reactivation

NOMIS Researcher(s)

Published in

July 1, 2020

During mitosis, transcription of genomic DNA is dramatically reduced, before it is reactivated during nuclear reformation in anaphase/telophase. Many aspects of the underlying principles that mediate transcriptional memory and reactivation in the daughter cells remain unclear. Here, we used ChIP-seq on synchronized cells at different stages after mitosis to generate genome-wide maps of histone modifications. Combined with EU-RNA-seq and Hi-C analyses, we found that during prometaphase, promoters, enhancers, and insulators retain H3K4me3 and H3K4me1, while losing H3K27ac. Enhancers globally retaining mitotic H3K4me1 or locally retaining mitotic H3K27ac are associated with cell type-specific genes and their transcription factors for rapid transcriptional activation. As cells exit mitosis, promoters regain H3K27ac, which correlates with transcriptional reactivation. Insulators also gain H3K27ac and CCCTC-binding factor (CTCF) in anaphase/telophase. This increase of H3K27ac in anaphase/telophase is required for posttranscriptional activation and may play a role in the establishment of topologically associating domains (TADs). Together, our results suggest that the genome is reorganized in a sequential order, in which histone methylations occur first in prometaphase, histone acetylation, and CTCF in anaphase/telophase, transcription in cytokinesis, and long-range chromatin interactions in early G1. We thus provide insights into the histone modification landscape that allows faithful reestablishment of the transcriptional program and TADs during cell division.

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

DOI
10.1101/GAD.335794.119

Baseline demographic, clinical, and cognitive characteristics of the Alzheimer’s Prevention Initiative (API) Autosomal-Dominant Alzheimer’s Disease Colombia Trial

NOMIS Researcher(s)

Published in

July 1, 2020

Introduction: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo-controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60-year-old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non-carriers who receive placebo. Methods: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non-carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non-carriers, 30 to 53 years of age. Carriers were significantly younger than non-carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non-carriers. Their demographic characteristics are representative of the local population.

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

DOI
10.1002/alz.12109

Systematic review and analysis of human proteomics aging studies unveils a novel proteomic aging clock and identifies key processes that change with age

NOMIS Researcher(s)

Published in

July 1, 2020

The development of clinical interventions that significantly improve human healthspan requires robust markers of biological age as well as thoughtful therapeutic targets. To promote these goals, we performed a systematic review and analysis of human aging and proteomics studies. The systematic review includes 36 different proteomics analyses, each of which identified proteins that significantly changed with age. We discovered 1,128 proteins that had been reported by at least two or more analyses and 32 proteins that had been reported by five or more analyses. Each of these 32 proteins has known connections relevant to aging and age-related disease. GDF15, for example, extends both lifespan and healthspan when overexpressed in mice and is additionally required for the anti-diabetic drug metformin to exert beneficial effects on body weight and energy balance. Bioinformatic enrichment analyses of our 1,128 commonly identified proteins heavily implicated processes relevant to inflammation, the extracellular matrix, and gene regulation. We additionally propose a novel proteomic aging clock comprised of proteins that were reported to change with age in plasma in three or more different studies. Using a large patient cohort comprised of 3,301 subjects (aged 18–76 years), we demonstrate that this clock is able to accurately predict human age.

Research field(s)
Health Sciences, Public Health & Health Services, Gerontology

DOI
10.1016/j.arr.2020.101070

Prion infection, transmission, and cytopathology modeled in a low-biohazard human cell line

NOMIS Researcher(s)

Published in

June 30, 2020

Transmission of prion infectivity to susceptible murine cell lines has simplified prion titration assays and has greatly reduced the need for animal experimentation. However, murine cell models suffer from technical and biological constraints. Human cell lines might be more useful, but they are much more biohazardous and are often poorly infectible. Here, we describe the human clonal cell line hovS, which lacks the human PRNP gene and expresses instead the ovine PRNP VRQ allele. HovS cells were highly susceptible to the PG127 strain of sheep-derived murine prions, reaching up to 90% infected cells in any given culture and were maintained in a continuous infected state for at least 14 passages. Infected hovS cells produced proteinase K–resistant prion protein (PrPSc), pelletable PrP aggregates, and bona fide infectious prions capable of infecting further generations of naïve hovS cells and mice expressing the VRQ allelic variant of ovine PrPC. Infection in hovS led to prominent cytopathic vacuolation akin to the spongiform changes observed in individuals suffering from prion diseases. In addition to expanding the toolbox for prion research to human experimental genetics, the hovS cell line provides a human-derived system that does not require human prions. Hence, the manipulation of scrapie-infected hovS cells may present fewer biosafety hazards than that of genuine human prions.

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

DOI
10.26508/LSA.202000814

In vivo activation of a conserved microRNA program induces mammalian heart regeneration

NOMIS Researcher(s)

Published in

June 26, 2020

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.

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

DOI
10.1016/j.stem.2014.10.003

Cryo-Electron Tomography Reveals the Complex Ultrastructural Organization of Multicellular Filamentous Chloroflexota (Chloroflexi) Bacteria

NOMIS Researcher(s)

Published in

June 26, 2020

The cell biology of Chloroflexota is poorly studied. We applied cryo-focused ion beam milling and cryo-electron tomography to study the ultrastructural organization of thermophilic Roseiflexus castenholzii and Chloroflexus aggregans, and mesophilic “Ca. Viridilinea mediisalina.” These species represent the three main lineages within a group of multicellular filamentous anoxygenic phototrophic Chloroflexota bacteria belonging to the Chloroflexales order. We found surprising structural complexity in the Chloroflexales. As with filamentous cyanobacteria, cells of C. aggregans and “Ca. Viridilinea mediisalina” share the outer membrane-like layers of their intricate multilayer cell envelope. Additionally, cells of R. castenholzii and “Ca. Viridilinea mediisalina” are connected by septal channels that resemble cyanobacterial septal junctions. All three strains possess long pili anchored close to cell-to-cell junctions, a morphological feature comparable to that observed in cyanobacteria. The cytoplasm of the Chloroflexales bacteria is crowded with intracellular organelles such as different types of storage granules, membrane vesicles, chlorosomes, gas vesicles, chemoreceptor-like arrays, and cytoplasmic filaments. We observed a higher level of complexity in the mesophilic strain compared to the thermophilic strains with regards to the composition of intracellular bodies and the organization of the cell envelope. The ultrastructural details that we describe in these Chloroflexales bacteria will motivate further cell biological studies, given that the function and evolution of the many discovered morphological traits remain enigmatic in this diverse and widespread bacterial group.

Research field(s)
Health Sciences, Biomedical Research, Microbiology

DOI
10.3389/fmicb.2020.01373

Reversing a model of Parkinson’s disease with in situ converted nigral neurons

NOMIS Researcher(s)

Published in

June 25, 2020

Parkinson’s disease is characterized by loss of dopamine neurons in the substantia nigra1. Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson’s disease. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits2. Here we report an efficient one-step conversion of isolated mouse and human astrocytes to functional neurons by depleting the RNA-binding protein PTB (also known as PTBP1). Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits. Astrocytes from different brain regions are converted to different neuronal subtypes. Using a chemically induced model of Parkinson’s disease in mouse, we show conversion of midbrain astrocytes to dopaminergic neurons, which provide axons to reconstruct the nigrostriatal circuit. Notably, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. A similar reversal of disease phenotype is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible approach to treating neurodegeneration by replacing lost neurons.

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

DOI
10.1038/s41586-020-2388-4

Nuclear Periphery Takes Center Stage: The Role of Nuclear Pore Complexes in Cell Identity and Aging

NOMIS Researcher(s)

Published in

June 17, 2020

In recent years, the nuclear pore complex (NPC) has emerged as a key player in genome regulation and cellular homeostasis. New discoveries have revealed that the NPC has multiple cellular functions besides mediating the molecular exchange between the nucleus and the cytoplasm. In this review, we discuss non-transport aspects of the NPC focusing on the NPC-genome interaction, the extreme longevity of the NPC proteins, and NPC dysfunction in age-related diseases. The examples summarized herein demonstrate that the NPC, which first evolved to enable the biochemical communication between the nucleus and the cytoplasm, now doubles as the gatekeeper of cellular identity and aging. Cho and Hetzer discuss recent studies that have established the nuclear pore complex as a key regulator of transcription control of cell identity genes and have linked its functional decline to premature, physiological, and pathological aging.

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

DOI
10.1016/j.neuron.2020.05.031

Genome-wide transcriptomics identifies an early preclinical signature of prion infection

NOMIS Researcher(s)

Published in

June 1, 2020

The clinical course of prion diseases is accurately predictable despite long latency periods, suggesting that prion pathogenesis is driven by precisely timed molecular events. We constructed a searchable genome-wide atlas of mRNA abundance and splicing alterations during the course of disease in prion-inoculated mice. Prion infection induced PrP-dependent transient changes in mRNA abundance and processing already at eight weeks post inoculation, well ahead of any neuropathological and clinical signs. In contrast, microglia-enriched genes displayed an increase simultaneous with the appearance of clinical signs, whereas neuronal-enriched transcripts remained unchanged until the very terminal stage of disease. This suggests that glial pathophysiology, rather than neuronal demise, could be the final driver of disease. The administration of young plasma attenuated the occurrence of early mRNA abundance alterations and delayed signs in the terminal phase of the disease. The early onset of prion-induced molecular changes might thus point to novel biomarkers and potential interventional targets.

Research field(s)
Health Sciences, Biomedical Research, Virology

DOI
10.1371/journal.ppat.1008653

Copathology in Progressive Supranuclear Palsy: Does It Matter?

NOMIS Researcher(s)

Published in

June 1, 2020

Background: The influence of concomitant brain pathologies on the progression rate in PSP is unclear. Objectives: To analyze the frequency and severity of copathologies and their impact on the progression in PSP. Methods: We analyzed clinic-pathological features of 101 PSP patients. Diagnoses and stages of copathologies were established according to standardized criteria, including Alzheimer’s disease–related pathology, argyrophilic grains, Lewy-related pathology, transactive response DNA-binding protein 43 pathology, fused in sarcoma pathology, cerebral amyloid angiopathy, and small vessel disease. Demographic data and major clinical milestones (frequency and latency to onset) were extracted from patients’ files. Results: Only 8% of 101 patients presented with pure PSP pathology without any copathology. Alzheimer’s disease–related pathology was the most frequent (84%), followed by argyrophilic grains (58%), both occurring as single copathology or in combination with other proteinopathies or cerebrovascular disease. Lewy-related and transactive response DNA-binding protein 43 copathology occurred rarely (8% and 6%, respectively). Fused in sarcoma–positive cases were not found. While being common, copathology was mostly mild in severity, with the exception of frequently widespread argyrophilic grains. Small vessel disease was also frequent (65%). Cerebral amyloid angiopathy occurred only in the presence of Alzheimer’s disease–related changes (25%). The copathologies did not have major impact on prevalence and time frame of major disease milestones. Conclusions: In PSP, concomitant neurodegenerative proteinopathies or cerebrovascular diseases are frequent, but generally mild in severity. Our data confirmed that four repeat tau is still the most relevant target for PSP, whereas the impact of copathologies on progression rate appears to be of less importance. This is relevant information for the development of disease-modifying therapies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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

DOI
10.1002/mds.28011

Plasma neurofilament light chain in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional and longitudinal cohort study

NOMIS Researcher(s)

Published in

June 1, 2020

Background: Neurofilament light chain (NfL) is a promising biomarker of active axonal injury and neuronal degeneration. We aimed to characterise cross-sectional and longitudinal plasma NfL measurements and determine the age at which NfL concentrations begin to differentiate between carriers of the presenilin 1 (PSEN1) E280A (Glu280Ala) mutation and age-matched non-carriers from the Colombian autosomal dominant Alzheimer’s disease kindred. Methods: In this cross-sectional and longitudinal cohort study, members of the familial Alzheimer’s disease Colombian kindred aged 8–75 years with no other neurological or health conditions were recruited from the Alzheimer’s Prevention Initiative Registry at the University of Antioquia (Medellín, Colombia) between Aug 1, 1995, and Dec 15, 2018. We used a single molecule array immunoassay and log-transformed data to examine the relationship between plasma NfL concentrations and age, and establish the earliest age at which NfL concentrations begin to diverge between mutation carriers and non-carriers. Findings: We enrolled a cohort of 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments; of these participants, longitudinal measures (with a mean follow-up of 6 years) were available for 242 mutation carriers and 262 non-carriers. Plasma NfL measurements increased with age in both groups (p<0·0001), and began to differentiate carriers from non-carriers when aged 22 years (22 years before the estimated median age at mild cognitive impairment onset of 44 years), although the ability of plasma NfL to discriminate between carriers and non-carriers only reached high sensitivity close to the age of clinical onset. Interpretation: Our findings further support the promise of plasma NfL as a biomarker of active neurodegeneration in the detection and tracking of Alzheimer's disease and the evaluation of disease-modifying therapies. Funding: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Banner Alzheimer's Foundation, COLCIENCIAS, the Torsten Söderberg Foundation, the Swedish Research Council, the Swedish Alzheimer Foundation, the Swedish Brain Foundation, and the Swedish state under the ALF-agreement.

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

DOI
10.1016/S1474-4422(20)30137-X

Do you hear what I see? An audio-visual paradigm to assess emotional egocentricity bias

NOMIS Researcher(s)

Published in

May 18, 2020

We often use our own emotions to understand other people’s emotions. However, emotional egocentric biases (EEB), namely the tendency to use one’s own emotional state when relating to others’ emotions, may hinder this process, especially when emotions are incongruent. We capitalised on the classic EEB task to develop a new version that is easier to implement and control. Unlike the original EEB task that relies on a combination of private (e.g. touch) and public (e.g. vision) sensory information, our EEB task (AV-EEB) used audio-visual stimuli to evoke congruent/incongruent emotions in participants. Auditory and visual signals are both public, in that they can be shared among individuals, and make the task easier to implement and control. We provide lab-based and online validations of the AV-EEB, and demonstrate a positive relationship between EEB and social negative potency. This new, easily implemented version of the EEB task can accelerate the investigation of egocentricity biases in several research areas.

Research field(s)
Health Sciences, Psychology & Cognitive Sciences, Social Psychology

DOI
10.1080/02699931.2019.1683516

A CRISPR view on autophagy

NOMIS Researcher(s)

Published in

May 1, 2020

Autophagy is a fundamental pathway for the degradation of cytoplasmic content in response to pleiotropic extracellular and intracellular stimuli. Recent advances in the autophagy field have demonstrated that different organelles can also be specifically targeted for autophagy with broad implications on cellular and organismal health. This opens new dimensions in the autophagy field and more unanswered questions on the rationale and underlying mechanisms to degrade different organelles. Functional genomics via clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9-based screening has gained popularity in the autophagy field to understand the common and unique factors that are implicated in the signaling, recognition, and execution of different cargo-specific autophagies. We focus on recent applications of CRISPR-based screens in the autophagy field, their discoveries, and the future directions of autophagy screens.

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

DOI
10.1016/j.tcb.2022.04.006

Microwave quantum illumination using a digital receiver

NOMIS Researcher(s)

Published in

May 1, 2020

Quantum illumination uses entangled signal-idler photon pairs to boost the detection efficiency of low-reflectivity objects in environments with bright thermal noise. Its advantage is particularly evident at low signal powers, a promising feature for applications such as noninvasive biomedical scanning or low-power short-range radar. Here, we experimentally investigate the concept of quantum illumination at microwave frequencies. We generate entangled fields to illuminate a room-temperature object at a distance of 1 m in a free-space detection setup. We implement a digital phase-conjugate receiver based on linear quadrature measurements that outperforms a symmetric classical noise radar in the same conditions, despite the entanglement-breaking signal path. Starting from experimental data, we also simulate the case of perfect idler photon number detection, which results in a quantum advantage compared with the relative classical benchmark. Our results highlight the opportunities and challenges in the way toward a first room-temperature application of microwave quantum circuits.

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

DOI
10.1126/sciadv.abb0451

Disease-modifying strategies in primary tauopathies

NOMIS Researcher(s)

Published in

May 1, 2020

Tauopathies are neurodegenerative brain diseases that are characterized by the formation of intraneuronal inclusions containing the microtubule-associated protein tau. This major hallmark defines tau pathology which is predominant in primary tauopathies, while in secondary forms additional driving forces are involved. In the course of the disease, different brain areas degenerate and lead to severe defects of language, behavior and movement. Although neuropathologically heterogeneous, primary tauopathies share a common feature, which is the generation of abnormal tau species that aggregate and progress into filamentous deposits in neurons. Mechanisms that are involved in this disease-related process offer a broad range of targets for disease-modifying therapeutics. The present review provides an up-to-date overview of currently known targets in primary tauopathies and their possible therapeutic modulation. It is structured into four major targets, the post-translational modifications of tau and tau aggregation, protein homeostasis, disease propagation, and tau genetics. Chances, as well as obstacles in the development of effective therapies are highlighted. Some therapeutic strategies, e.g., passive or active immunization, have already reached clinical development, raising hopes for affected patients. Other concepts, e.g., distinct modulators of proteostasis, are at the ready to be developed into promising future therapies. This article is part of the special issue entitled ‘The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders’.

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

DOI
10.1016/j.neuropharm.2019.107842

The Biology of Physiological Health

NOMIS Researcher(s)

Published in

April 16, 2020

In this Perspective, Janelle Ayres argues for a paradigm shift in how we think about “health,” toward viewing it as an active process involving mechanisms distinct from those of disease.

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

DOI
10.1016/j.cell.2020.03.036

Cell-to-cell transmission of C9orf72 poly-(Gly-Ala) triggers key features of ALS/FTD

NOMIS Researcher(s)

Published in

April 15, 2020

The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development. Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

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

DOI
10.15252/embj.2019102811

Child health as human capital

NOMIS Researcher(s)

Published in

April 1, 2020

Child health is increasingly understood to be a critical form of human capital, but only recently have we begun to understand how valuable it is and how its development could be better supported. This article provides an overview of recent work that demonstrates the key role of public insurance in supporting longer term human capital development and points to improvements in child mental health as an especially important mechanism.

Research field(s)
Health Sciences, Public Health & Health Services, Health Policy & Services

DOI
10.1002/hec.3995

Phase separation directs ubiquitination of gene-body nucleosomes

NOMIS Researcher(s)

Published in

March 26, 2020

The conserved yeast E3 ubiquitin ligase Bre1 and its partner, the E2 ubiquitin-conjugating enzyme Rad6, monoubiquitinate histone H2B across gene bodies during the transcription cycle1. Although processive ubiquitination might—in principle—arise from Bre1 and Rad6 travelling with RNA polymerase II2, the mechanism of H2B ubiquitination across genic nucleosomes remains unclear. Here we implicate liquid–liquid phase separation3 as the underlying mechanism. Biochemical reconstitution shows that Bre1 binds the scaffold protein Lge1, which possesses an intrinsically disordered region that phase-separates via multivalent interactions. The resulting condensates comprise a core of Lge1 encapsulated by an outer catalytic shell of Bre1. This layered liquid recruits Rad6 and the nucleosomal substrate, which accelerates the ubiquitination of H2B. In vivo, the condensate-forming region of Lge1 is required to ubiquitinate H2B in gene bodies beyond the +1 nucleosome. Our data suggest that layered condensates of histone-modifying enzymes generate chromatin-associated ‘reaction chambers’, with augmented catalytic activity along gene bodies. Equivalent processes may occur in human cells, and cause neurological disease when impaired.

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

DOI
10.1038/s41586-020-2097-z

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