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| Open AccessPopulation-scale long-read sequencing uncovers transposable elements associated with gene expression variation and adaptive signatures in Drosophila
Even in well-studied species, there is still substantial natural genetic variation that has not been characterized. Here, the authors use long read sequencing to discover transposable elements in the Drosophila genome not detected by short read sequencing, and link them to gene expression.
- Gabriel E. Rech
- , Santiago Radío
- & Josefa González
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Article
| Open AccessA natural timeless polymorphism allowing circadian clock synchronization in “white nights”
The genus Drosophila originate in subSaharan Africa and spread North up to the polar circle where they experience long days in the summer or even constant light. Here, the authors show that a form of the TIMELESS protein enables flies to synchronise their behavioural activity to long summer days
- Angelique Lamaze
- , Chenghao Chen
- & Ralf Stanewsky
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Article
| Open AccessNasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
- Satria P. Sajuthi
- , Jamie L. Everman
- & Max A. Seibold
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Article
| Open AccessA genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome
The underlying genetics of carpal tunnel syndrome is not well understood. Here, the authors perform a GWAS meta-analysis for carpal tunnel syndrome finding variants at 50 loci with connections to the extracellular matrix discovered through various functional analyses.
- Astros Th. Skuladottir
- , Gyda Bjornsdottir
- & Kari Stefansson
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Article
| Open AccessOncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia
‘Mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with poor clinical outcome, however, their impact on chromatin dynamics remains unexplored. Here the authors use a multi-omics approach for chronic myelomonocytic leukemia (CMML) and investigate the transcriptome and chromatin landscape of ASXL1MT CMML.
- Moritz Binder
- , Ryan M. Carr
- & Mrinal M. Patnaik
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Article
| Open AccessComprehensive evaluation of deconvolution methods for human brain gene expression
Transcriptome deconvolution aims to estimate cellular composition based on gene expression data. Here the authors evaluate deconvolution methods for human brain transcriptome and conclude that partial deconvolution algorithms work best, but that appropriate cell-type signatures are also important.
- Gavin J. Sutton
- , Daniel Poppe
- & Irina Voineagu
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Article
| Open AccessDNA methylation-free Arabidopsis reveals crucial roles of DNA methylation in regulating gene expression and development
Our understanding of the extent of involvement of DNA methylation in genome-wide gene regulation and plant developmental control is incomplete. Here, the authors knock out all five known DNA methyltransferases and show the developmental and gene expression changes in the DNA methylation-free Arabidopsis plants.
- Li He
- , Huan Huang
- & Jian-Kang Zhu
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Article
| Open AccessKastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis
A number of testes-specific lncRNAs have been annotated but their roles remain largely unexplored. Here the authors identify two small peptides encoded by the lncRNA Gm9999, Kastor and Polluks, both of which are required for male fertility in mice.
- Shintaro Mise
- , Akinobu Matsumoto
- & Keiichi I. Nakayama
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Article
| Open AccessKansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with Koolen-de Vries syndrome in mice
Here the authors show that the Koolen-de Vries syndrome associated gene KANSL1 modulates autophagosome-lysosome fusion via transcriptional regulation of autophagosomal gene Syntaxin17, and that 13-cis retinoic acid can reverses mitophagic defects and neurobehavioural abnormalities of mice lacking Kansl1.
- Ting Li
- , Dingyi Lu
- & Xin Pan
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Article
| Open AccessSpatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium
Through regeneration, the endometrium accumulates somatic mutations that can lead to diseases like endometriosis and cancer. Here, the authors use genomics to analyse normal endometrial glands from different patient cohorts, detect rhizome structures with common clonal ancestors and infer clonal expansion dynamics.
- Manako Yamaguchi
- , Hirofumi Nakaoka
- & Takayuki Enomoto
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Article
| Open AccessSM-Omics is an automated platform for high-throughput spatial multi-omics
The spatial organisation of cells and molecules plays a key role in tissue function. Here the authors report Spatial MultiOmics (SM-Omics) as a fully automated, high-throughput all-sequencing based platform for combined and spatially resolved transcriptomics and antibody-based protein measurements.
- S. Vickovic
- , B. Lötstedt
- & A. Regev
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Article
| Open AccessPlacental genomics mediates genetic associations with complex health traits and disease
The impact of placental transcriptomics on fetal traits throughout development is not well understood. Here, the authors apply distal-SNP-enriched transcriptome-wide association studies to detect genetic contributions, mediated through fetal placental genomics, to developmental programming of complex traits across the life course.
- Arjun Bhattacharya
- , Anastasia N. Freedman
- & Hudson P. Santos Jr
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Article
| Open AccessTissue-specific multi-omics analysis of atrial fibrillation
Numerous disease-associated variants have been described in GWAS for atrial fibrillation. Here the authors integrate omics data to investigate the consequences of genetic variants for transcript and protein levels in the atrium of the human heart. With this multi-omics approach, authors reveal the regulatory network underlying atrial fibrillation and provide a resource for cardiac gene prioritization.
- Ines Assum
- , Julia Krause
- & Matthias Heinig
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Article
| Open AccessMutations in Hcfc1 and Ronin result in an inborn error of cobalamin metabolism and ribosomopathy
Combined methylmalonic acidemia (MMA) and hyperhomocysteinemias are inborn errors of vitamin B12 metabolism, and mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) underlie some forms of these disorders. Here the authors generated mouse models of a human syndrome due to mutations in RONIN (THAP11) and HCFC1, and show that this syndrome is both an inborn error of vitamin B12 metabolism and displays some features of ribosomopathy.
- Tiffany Chern
- , Annita Achilleos
- & Ross A. Poché
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Article
| Open AccessIntegrating gene expression and clinical data to identify drug repurposing candidates for hyperlipidemia and hypertension
Prioritizing drug repurposing candidates for downstream studies remains challenging. Here, the authors present a high-throughput approach to identify and validate drug repurposing candidates, integrating human gene expression, drug perturbation, and clinical data from publicly available resources.
- Patrick Wu
- , QiPing Feng
- & Wei-Qi Wei
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Article
| Open AccessA transposon expression burst accompanies the activation of Y-chromosome fertility genes during Drosophila spermatogenesis
In this study, Lawlor et al. show that transposons on the Drosophila Y chromosome have evolved to exploit a specific stage of spermatogenesis when the Y chromosome is decondensed and the piRNA pathway is downregulated.
- Matthew A. Lawlor
- , Weihuan Cao
- & Christopher E. Ellison
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| Open AccessHeterogeneous recruitment abilities to RNA polymerases generate nonlinear scaling of gene expression with cell volume
Expression levels of most genes are proportional to cell volumes, although some genes exhibit nonlinear scaling of expression levels with cell volume. Here the authors provide a model that reveals nonlinear scaling is a direct consequence of heterogeneous recruitment abilities of promoters to RNA polymerases.
- Qirun Wang
- & Jie Lin
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Article
| Open AccessA somatic proteoglycan controls Notch-directed germ cell fate
Notch receptor GLP-1 is required for maintaining germ cells in the C. elegans germline. Here the authors show that syndecan-1, a somatic transmembrane proteoglycan regulates expression of glp-1 and germ cell mitosis in C. elegans, by promoting calcium-dependent binding of APTF-2 to the glp-1 promoter.
- Sandeep Gopal
- , Aqilah Amran
- & Roger Pocock
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Article
| Open AccessJumper enables discontinuous transcript assembly in coronaviruses
@melkebir @psashittal et al. develop a graph-based method for the assembly of discontinuous transcripts produced in Coronaviruses and other Nidovirales, enabling the discovery of transcriptional changes missed by existing methods.
- Palash Sashittal
- , Chuanyi Zhang
- & Mohammed El-Kebir
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Article
| Open AccessMolecular programs of fibrotic change in aging human lung
Age is associated with increasing vulnerability to both acute and chronic lung diseases. Employing genomic analysis and live lung imaging, this study reveals a profile of increased cellular senescence, telomere shortening, and fibrosis-induced impaired alveolar function in the natural history of human lung aging.
- Seoyeon Lee
- , Mohammad Naimul Islam
- & Mallar Bhattacharya
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Article
| Open AccessPHF3 regulates neuronal gene expression through the Pol II CTD reader domain SPOC
Here the authors identify PHF3 SPOC domain as a reader of the phosphorylated RNA polymerase II (Pol II) C-terminal domain. They show that PHF3 clusters with Pol II complexes in cells, drives phase separation of Pol II in vitro, and regulates neuronal gene expression and neuronal differentiation.
- Lisa-Marie Appel
- , Vedran Franke
- & Dea Slade
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Article
| Open AccessThe transcription factor NF-Y participates to stem cell fate decision and regeneration in adult skeletal muscle
Satellite cells represent myogenic stem cells that allow the homeostasis and repair of adult skeletal muscle. Here the authors report that the transcription factor NF-Y is expressed in satellite cells and is important for their maintenance and proper myogenic differentiation.
- Giovanna Rigillo
- , Valentina Basile
- & Carol Imbriano
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Article
| Open AccessPig genome functional annotation enhances the biological interpretation of complex traits and human disease
Annotating functional elements of the genome helps the interpretation of genetic variation. Here, the authors compile functional genomics data for the pig genome over 14 tissues with 15 different chromatin states, integrate the data with WGS and GWAS data, and compare conservation of regulatory elements across mouse and human tissues.
- Zhangyuan Pan
- , Yuelin Yao
- & Huaijun Zhou
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Article
| Open AccessCHARGE syndrome protein CHD7 regulates epigenomic activation of enhancers in granule cell precursors and gyrification of the cerebellum
CHARGE syndrome that affects cerebellar development can be caused by haploinsufficiency of the chromatin remodeling enzyme CHD7; however the precise role of CHD7 remains unknown. Here the authors show CHD7 promotes chromatin accessibility and enhancer activity in granule cell precursors and regulates morphogenesis of the cerebellar cortex, where loss of CHD7 triggers cerebellar polymicrogyria.
- Naveen C. Reddy
- , Shahriyar P. Majidi
- & Harrison W. Gabel
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Article
| Open AccessDifferentially expressed genes reflect disease-induced rather than disease-causing changes in the transcriptome
Identification of gene expression changes between healthy and diseased individuals can reveal mechanistic insights and biomarkers. Here, the authors propose a bi-directional transcriptome-wide Mendelian Randomization approach to assess causal effects between gene expression and complex traits.
- Eleonora Porcu
- , Marie C. Sadler
- & Zoltán Kutalik
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| Open AccessDissecting transition cells from single-cell transcriptome data through multiscale stochastic dynamics
How to infer transient cells and cell-fate transitions from snap-shot single cell transcriptome dataset remains a major challenge. Here the authors present a multiscale approach to construct single-cell dynamical manifold, quantify cell stability, and compute transition trajectory and probability between cell states.
- Peijie Zhou
- , Shuxiong Wang
- & Qing Nie
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Article
| Open AccessSpatial regulation by multiple Gremlin1 enhancers provides digit development with cis-regulatory robustness and evolutionary plasticity
The BMP antagonist Gremlin1 balances BMP and SHH signalling, endowing limb bud development with robustness. Here, the authors identify enhancers controlling Grem1 levels in an additive, and spatial regulation in a synergistic manner, providing digit patterning with cis-regulatory robustness and evolutionary plasticity.
- Jonas Malkmus
- , Laurène Ramos Martins
- & Rolf Zeller
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Article
| Open AccessSingle-cell RNA sequencing of peripheral blood mononuclear cells from acute Kawasaki disease patients
Immune cell changes are associated with Kawasaki disease (KD) pathogenesis. Here, using single cell RNA sequencing of PBMC, the authors show monocyte inflammatory genes are over-expressed in KD and TCR and BCR clonotype sequences show oligoclonal expansions after intravenous immunoglobulin therapy.
- Zhen Wang
- , Lijian Xie
- & Min Huang
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Article
| Open AccessIntegrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma
TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare subtype of kidney cancer with no standard treatment options for the advanced disease. Here, the authors perform genomic and transcriptomic profiling of 63 untreated primary TFE3-tRCC tumours and reveal potential therapeutic targets.
- Guangxi Sun
- , Junru Chen
- & Hao Zeng
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Article
| Open AccessThe concurrence of DNA methylation and demethylation is associated with transcription regulation
The global pattern of the mammalian methylome is formed by changes in methylation and demethylation. Here the authors describe a metric methylation concurrence that measures the ratio of unmethylated CpGs inside the partially methylated reads and show that methylation concurrence is associated with epigenetically regulated tumour suppressor genes.
- Jiejun Shi
- , Jianfeng Xu
- & Wei Li
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Article
| Open AccessMulti-omics integration analysis identifies novel genes for alcoholism with potential overlap with neurodegenerative diseases
Alcohol use disorder and drinks per week both have been studied genetically and have different correlations with psychiatric diseases. Here the authors integrate multi-omics data to identify unique and shared variants, genes and pathways for alcohol use disorder and drinks per week.
- Manav Kapoor
- , Michael J. Chao
- & Alison Goate
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Article
| Open AccessHistone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes
The effect of histone H4 lysine 20 methylation (H4K20me) on chromatin accessibility are not well established. Here the authors show how H4K20 methylation regulates chromatin structure and accessibility to ensure precise transcriptional outputs through the cell cycle using genome-wide approaches, in vitro biophysical assays, and NMR.
- Muhammad Shoaib
- , Qinming Chen
- & Claus S. Sørensen
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Article
| Open AccessA unified model of human hemoglobin switching through single-cell genome editing
Genetic mechanisms underlying fetal hemoglobin (HbF) regulation and switching are not fully understood. Here, the authors develop a single-cell genome editing functional assay to model how effects of mutation-harbouring functional elements contribute to HbF expression.
- Yong Shen
- , Jeffrey M. Verboon
- & Vijay G. Sankaran
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Article
| Open AccessLineageOT is a unified framework for lineage tracing and trajectory inference
Lineage tracing and snapshots of transcriptional state at the single-cell level are powerful, complementary tools for studying development. Here, the authors propose a mathematical method combining lineage tracing with trajectory inference to improve our understanding of development.
- Aden Forrow
- & Geoffrey Schiebinger
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Article
| Open AccessGLIS1 regulates trabecular meshwork function and intraocular pressure and is associated with glaucoma in humans
Dysfunction of the trabecular meshwork (TM) is the chief cause of elevated intraocular pressure, the major risk factor of glaucoma. Here, the authors identify the transcription factor, GLIS1, as a critical regulator of TM maintenance and intraocular pressure, and as a glaucoma risk gene.
- K. Saidas Nair
- , Chitrangda Srivastava
- & Anton M. Jetten
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Article
| Open AccessThe molecular basis, genetic control and pleiotropic effects of local gene co-expression
Local gene co-expression is found throughout the genome, but systematic analysis of these co-expressed genes is needed. Here, the authors identify local co-expressed genes in 49 tissues and characterize the genetic variants which may affect their expression and contribute to disease.
- Diogo M. Ribeiro
- , Simone Rubinacci
- & Olivier Delaneau
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Article
| Open AccessStochastic pausing at latent HIV-1 promoters generates transcriptional bursting
The ability of HIV to alternate between acute and latent forms is thought to rely on a transcriptional feedback loop where polymerase pausing is released by the viral protein Tat. Here, the authors show that viral genome transcription can occur in a burst-like stochastic manner in the absence of Tat.
- Katjana Tantale
- , Encar Garcia-Oliver
- & Edouard Bertrand
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Article
| Open AccessSingle-molecule, full-length transcript isoform sequencing reveals disease-associated RNA isoforms in cardiomyocytes
Alternative splicing generates RNA isoforms that contribute to phenotypic diversity. Here the authors perform single-molecule full-length RNA sequencing to identify disease-associated variant transcript isoforms.
- Chenchen Zhu
- , Jingyan Wu
- & Lars M. Steinmetz
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Article
| Open AccessPromoter G-quadruplexes and transcription factors cooperate to shape the cell type-specific transcriptome
G-quadruplex (G4) structures play complex roles linked to transcription regulation. Here the authors, by comparing G4 location and transcript levels in liposarcoma and keratinocyte cells, reveal that G4s cooperate with transcription factors to determine cell-specific transcriptional programs.
- Sara Lago
- , Matteo Nadai
- & Sara N. Richter
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Article
| Open AccessGenomic imprinting in mouse blastocysts is predominantly associated with H3K27me3
In most mammals, imprinted genes contain epigenetic marks that differ in each parental genome and control their parent-of-origin-specific expression. Here, the authors map imprinted genes in mouse preimplantation embryos and find that imprinted gene expression in blastocysts is mainly dependent on Polycomb-mediated H3K27me3-associated gene silencing.
- Laura Santini
- , Florian Halbritter
- & Martin Leeb
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Article
| Open AccessA gain-of-function single nucleotide variant creates a new promoter which acts as an orientation-dependent enhancer-blocker
The role of promoters as potential insulator elements has been largely unexplored in mammals. Here the authors show that a single nucleotide variant in the α-globin locus forms a new promoter and acts as an orientation-dependent enhancer-blocking insulator element.
- Yavor K. Bozhilov
- , Damien J. Downes
- & Douglas R. Higgs
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Article
| Open AccessA pig BodyMap transcriptome reveals diverse tissue physiologies and evolutionary dynamics of transcription
A comprehensive transcriptomic survey of the pig could enable mechanistic understanding of tissue specialization and accelerate its use as a biomedical model. Here the authors characterize four distinct transcript types in 31 adult pig tissues to dissect their distinct structural and transcriptional features and uncover transcriptomic variability related to tissue physiology.
- Long Jin
- , Qianzi Tang
- & Mingzhou Li
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Article
| Open AccessBRN2 is a non-canonical melanoma tumor-suppressor
The transcription factor BRN2 regulates melanoma migration and invasion, but its role during melanoma initiation is unclear. Here the authors show that BRN2 is a haplo-insufficient tumour suppressor that positively regulates PTEN expression and in the context of BRAF mutation and heterozygous PTEN, BRN2 loss promotes melanoma initiation and progression.
- Michael Hamm
- , Pierre Sohier
- & Lionel Larue
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Article
| Open AccessModel-based prediction of spatial gene expression via generative linear mapping
Single cell RNA-seq loses spatial information of gene expression in multicellular systems because tissue must be dissociated. Here, the authors show the spatial gene expression profiles can be both accurately and robustly reconstructed by a new computational method using a generative linear mapping, Perler.
- Yasushi Okochi
- , Shunta Sakaguchi
- & Honda Naoki
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Article
| Open AccessReplicate sequencing libraries are important for quantification of allelic imbalance
Allele-specific expression in diploid organisms can be quantified by RNA-seq and it is common practice to rely on a single library. Here, the authors show that the standard approach has variable error rate and present Qllelic as a tool to improve reproducibility of allele-specific RNA-seq analysis.
- Asia Mendelevich
- , Svetlana Vinogradova
- & Alexander A. Gimelbrant
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Article
| Open AccessLeveraging supervised learning for functionally informed fine-mapping of cis-eQTLs identifies an additional 20,913 putative causal eQTLs
Finding causal variants and genes from GWAS loci results remains a challenge. Here, the authors train a model to predict if a variant affects nearby gene expression, and apply the method to identify new possible causal eQTLs and mechanisms of GWAS loci.
- Qingbo S. Wang
- , David R. Kelley
- & Hilary K. Finucane
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Article
| Open AccessTemporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer
The heterogeneity of tumor evolution from AR-positive, adenocarcinoma to AR-negative, neuroendocrine prostate cancer (NEPC) is not fully characterized. Here the authors generate a mouse model to show that Rb1 loss and MYCN overexpression accelerates the progression to AR-negative NEPC and identify emergence of distinct subpopulations of NEPC cells.
- Nicholas J. Brady
- , Alyssa M. Bagadion
- & David S. Rickman
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Article
| Open AccessmiR-802 regulates Paneth cell function and enterocyte differentiation in the mouse small intestine
Homeostasis of the intestinal epithelium is crucial for the maintenance of the epithelial barrier. Here, the authors show that mir-802 ablation in the mouse intestine impairs enterocyte differentiation and glucose absorption, enhances Paneth cell function by increasing Tmed9-mediated defensin secretion, and increases epithelial cell turnover.
- Algera Goga
- , Büsra Yagabasan
- & Markus Stoffel
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Article
| Open AccessTranscriptional signature in microglia associated with Aβ plaque phagocytosis
Microglia associated with Aβ plaques may have a distinct transcriptional signature compared to those in plaque-free areas of the brain in Alzheimer’s disease (AD) models. Here the authors show that amyloid plaque phagocytosis is associated with a specific microglia transcriptional signature in a mouse model of AD.
- Alexandra Grubman
- , Xin Yi Choo
- & Jose M. Polo