The skin barrier is the body's first line of defence against environmental assaults, and is maintained by epithelial stem cells (EpSCs). Despite the vulnerability of EpSCs to inflammatory pressures, ...neither the primary response to inflammation nor its enduring consequences are well understood. Here we report a prolonged memory to acute inflammation that enables mouse EpSCs to hasten barrier restoration after subsequent tissue damage. This functional adaptation does not require skin-resident macrophages or T cells. Instead, EpSCs maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus. Upon a secondary challenge, genes governed by these domains are transcribed rapidly. Fuelling this memory is Aim2, which encodes an activator of the inflammasome. The absence of AIM2 or its downstream effectors, caspase-1 and interleukin-1β, erases the ability of EpSCs to recollect inflammation. Although EpSCs benefit from inflammatory tuning by heightening their responsiveness to subsequent stressors, this enhanced sensitivity probably increases their susceptibility to autoimmune and hyperproliferative disorders, including cancer.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Cell competition-the sensing and elimination of less fit 'loser' cells by neighbouring 'winner' cells-was first described in Drosophila. Although cell competition has been proposed as a selection ...mechanism to optimize tissue and organ development, its evolutionary generality remains unclear. Here, by using live imaging, lineage tracing, single-cell transcriptomics and genetics, we identify two cell competition mechanisms that sequentially shape and maintain the architecture of stratified tissue during skin development in mice. In the single-layered epithelium of the early embryonic epidermis, winner progenitors kill and subsequently clear neighbouring loser cells by engulfment. Later, as the tissue begins to stratify, the basal layer instead expels losers through upward flux of differentiating progeny. This cell competition switch is physiologically relevant: when it is perturbed, so too is barrier formation. Our findings show that cell competition is a selective force that optimizes vertebrate tissue function, and illuminate how a tissue dynamically adjusts cell competition strategies to preserve fitness as its architectural complexity increases during morphogenesis.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during ...homeostasis, stem cells of the epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement—granting privileges associated with both fates—is not only hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Investigating mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.
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•Stem cell lineage infidelity occurs transiently in wounds and persists in cancer•Wounds and cancer converge on lineage infidelity irrespective of stem cell origin•Lineage infidelity is governed by stress-induced transcription factors•Activation of oncogenic enhancers distinguishes cancer from wounds
Stem cell lineage infidelity occurs transiently in wounds and persists in cancer, driving wound repair and malignancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We are just beginning to understand how translational control affects tumour initiation and malignancy. Here we use an epidermis-specific, in vivo ribosome profiling strategy to investigate the ...translational landscape during the transition from normal homeostasis to malignancy. Using a mouse model of inducible SOX2, which is broadly expressed in oncogenic RAS-associated cancers, we show that despite widespread reductions in translation and protein synthesis, certain oncogenic mRNAs are spared. During tumour initiation, the translational apparatus is redirected towards unconventional upstream initiation sites, enhancing the translational efficiency of oncogenic mRNAs. An in vivo RNA interference screen of translational regulators revealed that depletion of conventional eIF2 complexes has adverse effects on normal but not oncogenic growth. Conversely, the alternative initiation factor eIF2A is essential for cancer progression, during which it mediates initiation at these upstream sites, differentially skewing translation and protein expression. Our findings unveil a role for the translation of 5' untranslated regions in cancer, and expose new targets for therapeutic intervention.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
Objective
The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease ...has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial DNA (mtDNA) rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA.
Methods
Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the midyear period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondrial diseases.
Results
The minimum prevalence rate for mtDNA mutations was 1 in 5,000 (20 per 100,000), comparable with our previously published prevalence rates. In this population, nuclear mutations were responsible for clinically overt adult mitochondrial disease in 2.9 per 100,000 adults.
Interpretation
Combined, our data confirm that the total prevalence of adult mitochondrial disease, including pathogenic mutations of both the mitochondrial and nuclear genomes (≈1 in 4,300), is among the commonest adult forms of inherited neurological disorders. These figures hold important implications for the evaluation of interventions, provision of evidence‐based health policies, and planning of future services. Ann Neurol 2015 Ann Neurol 2015;77:753–759
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aging manifests with architectural alteration and functional decline of multiple organs throughout an organism. In mammals, aged skin is accompanied by a marked reduction in hair cycling and ...appearance of bald patches, leading researchers to propose that hair follicle stem cells (HFSCs) are either lost, differentiate, or change to an epidermal fate during aging. Here, we employed single-cell RNA-sequencing to interrogate aging-related changes in the HFSCs. Surprisingly, although numbers declined, aging HFSCs were present, maintained their identity, and showed no overt signs of shifting to an epidermal fate. However, they did exhibit prevalent transcriptional changes particularly in extracellular matrix genes, and this was accompanied by profound structural perturbations in the aging SC niche. Moreover, marked age-related changes occurred in many nonepithelial cell types, including resident immune cells, sensory neurons, and arrector pili muscles. Each of these SC niche components has been shown to influence HF regeneration. When we performed skin injuries that are known to mobilize young HFSCs to exit their niche and regenerate HFs, we discovered that aged skin is defective at doing so. Interestingly, however, in transplantation assays in vivo, aged HFSCs regenerated HFs when supported with young dermis, while young HFSCs failed to regenerate HFs when combined with aged dermis. Together, our findings highlight the importance of SC:niche interactions and favor a model where youthfulness of the niche microenvironment plays a dominant role in dictating the properties of its SCs and tissue health and fitness.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Human mutations in the cardiac transcription factor gene TBX5 cause congenital heart disease (CHD), although the underlying mechanism is unknown. We report characterization of the endogenous TBX5 ...cardiac interactome and demonstrate that TBX5, long considered a transcriptional activator, interacts biochemically and genetically with the nucleosome remodeling and deacetylase (NuRD) repressor complex. Incompatible gene programs are repressed by TBX5 in the developing heart. CHD mis-sense mutations that disrupt the TBX5-NuRD interaction cause depression of a subset of repressed genes. Furthermore, the TBX5-NuRD interaction is required for heart development. Phylogenetic analysis showed that the TBX5-NuRD interaction domain evolved during early diversification of vertebrates, simultaneous with the evolution of cardiac septation. Collectively, this work defines a TBX5-NuRD interaction essential to cardiac development and the evolution of the mammalian heart, and when altered may contribute to human CHD.
•Isolation and characterization of the endogenous cardiac TBX5 interactome•TBX5 interacts biochemically and genetically with the NuRD repressor complex•TBX5 represses inappropriate gene programs incompatible with cardiac development•Human TBX5 mutations alter the NuRD interaction and correlate with septal defects
Waldron et al. isolate the cardiac interactome of TBX5, revealing that this transcription factor, implicated in congenital heart disease (CHD) and thought to be an activator, interacts with NuRD to repress inappropriate gene expression in the heart. CHD mutations disrupting the TBX5-NuRD interaction cause derepression of some of these genes.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Progression through the cell cycle is largely dependent on waves of periodic gene expression, and the regulatory networks for these transeriptome dynamics have emerged as critical points of ...vulnerability in various aspects of tumor biology. Through RNA-sequencing of human cells during two continuous cell cycles （〉2.3 billion paired reads）, we identified over 1 000 mRNAs, non-coding RNAs and pseudogenes with periodic expression. Periodic transcripts are enriched in functions related to DNA metabolism, mitosis, and DNA damage response, indicating these genes likely represent putative cell cycle regulators. Using our set of periodic genes, we developed a new approach termed ＂mitotic trait＂ that can classify primary tumors and normal tissues by their transcriptome similarity to different cell cycle stages. By analyzing 〉4 000 tumor samples in The Cancer Genome Atlas （TCGA） and other expression data sets, we found that mitotic trait significantly correlates with genetic alterations, tumor subtype and, notably, patient survival. We further defined a core set of 67 genes with robust periodic expression in multiple cell types. Proteins encoded by these genes function as major hubs of protein-protein interaction and are mostly required for cell cycle progression. The core genes also have unique chromatin features including increased levels of CTCF/RAD21 binding and H3K36me3. Loss of these features in uterine and kidney cancers is associated with altered expression of the core 67 genes. Our study suggests new chromatin-associated mechanisms for periodic gene regulation and offers a predictor of cancer patient outcomes.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Concerns surrounding concussions from impacts to the head necessitate research to generate new knowledge about ways to prevent them and reduce risk. In this paper, we report the relative temporal ...characteristics of the head resulting from neck muscle co-contraction and postural changes following a sudden force applied to the head in four different directions. In the two “prepared” conditions (i.e., co-contraction and postural), participants experienced impulsive forces to the head after hearing a warning. The warning given for the postural condition informed both the direction and timing of the impulsive force. Participants responded to the postural warning by altering their head posture, whereas in the co-contraction warning, the force direction was unknown to them, and they were asked to isometrically co-contract their neck muscles after the warning. Peak angular velocity reduced by 29% in sagittal extension, 18% in sagittal flexion, and 23% in coronal lateral flexion in prepared vs. unwarned conditions. Peak linear acceleration was attenuated by 15% in sagittal extension, 8% in sagittal flexion, and 18% in coronal lateral flexion in prepared vs. unwarned conditions. Changes in peak angular acceleration were not uniform. We also measured a significant delay in the peak angular velocity (22 vs. 44.8 ms) and peak angular acceleration (7 vs. 20 ms) after peak linear acceleration in prepared compared to unwarned conditions. An increase in muscle activation significantly reduced the peak angular velocity and linear acceleration. Gross head movement was significantly decreased with preparation. These findings suggest that a warning prior to impact can reduce head kinematics associated with injury.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Through recurrent bouts synchronous with the hair cycle, quiescent melanocyte stem cells (McSCs) become activated to generate proliferative progeny that differentiate into pigment-producing ...melanocytes. The signaling factors orchestrating these events remain incompletely understood. Here, we use single-cell RNA sequencing with comparative gene expression analysis to elucidate the transcriptional dynamics of McSCs through quiescence, activation, and melanocyte maturation. Unearthing converging signs of increased WNT and BMP signaling along this progression, we endeavored to understand how these pathways are integrated. Employing conditional lineage-specific genetic ablation studies in mice, we found that loss of BMP signaling in the lineage leads to hair graying due to a block in melanocyte maturation. We show that interestingly, BMP signaling functions downstream from activated McSCs and maintains WNT effector, transcription factor LEF1. Employing pseudotime analysis, genetics, and chromatin landscaping, we show that following WNT-mediated activation of McSCs, BMP and WNT pathways collaborate to trigger the commitment of proliferative progeny by fueling LEF1- and MITF-dependent differentiation. Our findings shed light upon the signaling interplay and timing of cues that orchestrate melanocyte lineage progression in the hair follicle and underscore a key role for BMP signaling in driving complete differentiation.
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