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| Open AccessPrioritization of potential causative genes for schizophrenia in placenta
The placenta has been proposed to be potentially relevant to schizophrenia risk. Here, the authors use the genetically predicted transcriptome to identify genes expressed in the placenta that could be involved in schizophrenia.
- Gianluca Ursini
- , Pasquale Di Carlo
- & Daniel R. Weinberger
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Article
| Open AccessThe NELF pausing checkpoint mediates the functional divergence of Cdk9
Promoter-proximal pausing by RNA Pol II is a key aspect of how gene expression is transcriptionally regulated in higher eukaryotes. Here the authors show that only NELF-mediated pausing enforces a strict early checkpoint for Cdk9 by efficiently shutting down gene transcription following loss of Cdk9.
- Michael DeBerardine
- , Gregory T. Booth
- & John T. Lis
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| Open AccessCap analogs with a hydrophobic photocleavable tag enable facile purification of fully capped mRNA with various cap structures
Removing immunogenic uncapped mRNA from transcribed mRNA can be challenging, but is critical in mRNA research and clinical applications such as vaccines. Here, authors develop hydrophobic photocaged tag-modified cap analogs, which can be used to separate capped mRNA from uncapped mRNA, with subsequent tag removal using photo-irradiation.
- Masahito Inagaki
- , Naoko Abe
- & Hiroshi Abe
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Article
| Open AccessmeQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans
Here, the authors performed a large-scale in-depth cis-meQTL mapping study in 961 African Americans from the GENOA study, investigating the co-regulation of methylation and gene expression in African Americans.
- Lulu Shang
- , Wei Zhao
- & Xiang Zhou
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Article
| Open AccessDependency of NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis
Transcriptional dysregulation contributes to tumor progression. Here the authors show that transcriptional complex NELF interacts with SLUG, and co-opts KAT2B, to promote the expression of epithelial-mesenchymal transition (EMT) and stemness-associated genes in breast cancer.
- Jieqiong Zhang
- , Zhenhua Hu
- & Wee-Wei Tee
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Article
| Open AccessAn interactive murine single-cell atlas of the lung responses to radiation injury
Radiation damages the healthy lung and triggers severe side effects. Here the authors provide a single cell atlas of the lung responses to radiation injury to explore the spatio-temporal dynamics of the mechanisms leading to radio-induced pulmonary fibrosis.
- Sandra Curras-Alonso
- , Juliette Soulier
- & Charles Fouillade
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Article
| Open AccessEnhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation
Heterotopic ossification is a disorder characterized by the transformation of soft tissue to bone. In this study the authors report heterotopic ossification in a child caused by enhancer hijacking at the ARHGAP36 gene, the ectopic activation by an enhancer that it not its own.
- Uirá Souto Melo
- , Jerome Jatzlau
- & Malte Spielmann
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| Open AccessChance promoter activities illuminate the origins of eukaryotic intergenic transcriptions
It is debated whether the pervasive intergenic transcription from eukaryotic genomes has functional significance. Here, Xu et al. find that only 1–5% of yeast intergenic transcription is unattributable to chance promoter activity or neighboring gene expression.
- Haiqing Xu
- , Chuan Li
- & Jianzhi Zhang
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Article
| Open AccessA defect in mitochondrial protein translation influences mitonuclear communication in the heart
The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.
- Feng Gao
- , Tian Liang
- & Jinghai Chen
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Article
| Open AccessEvolutionary conservation of the fidelity of transcription
The molecular mechanisms that ensure faithful transcription of genetic information are still unclear. Chung et al. identify various genes, alleles and processes that affect the fidelity of transcription multiple organisms, suggesting evolutionary conservation of fidelity factors, and compare the error rate of transcription among these species.
- Claire Chung
- , Bert M. Verheijen
- & Marc Vermulst
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| Open AccessOTTERS: a powerful TWAS framework leveraging summary-level reference data
Here, the authors present a TWAS framework OTTERS that adapts multiple polygenic risk score methods to estimate eQTL weights from summary-level eQTL data. Both simulation and real studies show OTTERS is powerful across a wide range of genetic architectures.
- Qile Dai
- , Geyu Zhou
- & Jingjing Yang
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Article
| Open AccessQuantitative analysis of C. elegans transcripts by Nanopore direct-cDNA sequencing reveals terminal hairpins in non trans-spliced mRNAs
C. elegans long read transcriptomic analysis provides evidence that non-trans-spliced mRNAs display a terminal a hairpin structure mimicking the Spliced Leader. This provides an explanation how the main maturation system might be bypassed.
- Florian Bernard
- , Delphine Dargère
- & Denis Dupuy
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Article
| Open AccessFine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease
The mechanisms underlying many genetic variants associated with human traits are often unknown. Here, the authors identify the developmental stage-, organ-, tissue- and cell type-specific associations between genetic variation and gene expression in cardiac tissues, and describe how these associations affect complex cardiac traits and disease.
- Matteo D’Antonio
- , Jennifer P. Nguyen
- & Kelly A. Frazer
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Article
| Open AccessAdaptive partitioning of a gene locus to the nuclear envelope in Saccharomyces cerevisiae is driven by polymer-polymer phase separation
Partitioning of active genes to the nuclear periphery is commonly observed but not understood. Here, the authors show that this process occurs by phase separation of transcriptionally active chromatin providing for efficient mRNA transport and memory.
- Lidice González
- , Daniel Kolbin
- & Stephen W. Michnick
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Article
| Open AccessSocial complexity, life-history and lineage influence the molecular basis of castes in vespid wasps
A key hypothesis for the evolution of division of labour in social insects is that a shared set of genes – a genetic toolkit - regulates reproductive castes across species. Here, the authors analyze brain transcriptomes from nine species of social wasps to identify the factors that shape this toolkit.
- Christopher Douglas Robert Wyatt
- , Michael Andrew Bentley
- & Seirian Sumner
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| Open AccessA CpG island-encoded mechanism protects genes from premature transcription termination
Here the authors discover that SET1 complexes function as transcription anti-termination factors that bind to CpG islands and protect low to moderately transcribed genes from the pervasive termination activity of the ZC3H4 complex.
- Amy L. Hughes
- , Aleksander T. Szczurek
- & Robert J. Klose
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Article
| Open AccessCorrelated evolution of social organization and lifespan in mammals
To elucidate the relationship between sociality and longevity, the authors perform phylogenetic and transcriptomic comparative analysis of mammals. They find that group-living species lived longer than solitary species and identify 31 genes, hormones, and immunity-related pathways involved in this connection.
- Pingfen Zhu
- , Weiqiang Liu
- & Xuming Zhou
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Article
| Open AccessSingle-cell analysis reveals prognostic fibroblast subpopulations linked to molecular and immunological subtypes of lung cancer
Fibroblast heterogeneity is a prominent but poorly understood feature of solid tumours. Here three major fibroblast subpopulations in non-small cell lung cancer are identified and characterised through single cell RNA-sequencing, multiplexed immunohistochemistry and digital cytometry.
- Christopher J. Hanley
- , Sara Waise
- & Gareth J. Thomas
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Article
| Open AccessMiXcan: a framework for cell-type-aware transcriptome-wide association studies with an application to breast cancer
Conventional transcriptome-wide association study (TWAS) approaches predict genetically regulated gene expression at the tissue level. Here, the authors develop a framework for cell-type-aware TWAS that predicts cell-type level expression from genotype data and identifies disease-associated genes with cell-type-specific effects.
- Xiaoyu Song
- , Jiayi Ji
- & Weiva Sieh
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| Open AccessThe transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice
Aggravation of liver steatosis shifts the hepatocellular death mode from apoptosis to necroptosis in acute and chronic liver damage. Here the authors report that the transcription factor ATF3 regulates this shift through the induction of RIPK3, a regulator of necroptosis.
- Yuka Inaba
- , Emi Hashiuchi
- & Hiroshi Inoue
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| Open AccessSpatial-ID: a cell typing method for spatially resolved transcriptomics via transfer learning and spatial embedding
Comprehensive annotating of cell types in spatially resolved transcriptomics to understand biological processes at the single cell level remains challenging. Here the authors introduce Spatial-ID, a supervision-based cell typing method, that combines the existing knowledge of reference single-cell RNA-seq data and the spatial information of spatially resolved transcriptomics data.
- Rongbo Shen
- , Lin Liu
- & Jianhua Yao
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| Open AccessLimited conservation in cross-species comparison of GLK transcription factor binding suggested wide-spread cistrome divergence
Unlike microbes and mammals, cistrome dynamics in plants remains unclear. Here, using GOLDEN2-LIKE (GLK) transcription factor as an example, the authors find that most GLK binding sites are species-specific and the binding divergence is caused by cis-variations through inter-species transformation experiment.
- Xiaoyu Tu
- , Sibo Ren
- & Silin Zhong
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Article
| Open AccessEvaluation of cutaneous immune response in a controlled human in vivo model of mosquito bites
Vector-borne pathogens are known to elicit immune response upon mosquito biting the host which is critically linked to the establishment of infection and pathogenesis of disease, yet the impact of the mosquito bite itself is not immunologically well-appreciated. Here the authors characterize the immune response to the mosquito vector Aedes aegypti in a controlled human in vivo challenge model and show the induction of a range of immune pathways and cell types.
- David Guerrero
- , Hoa Thi My Vo
- & Jessica E. Manning
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Article
| Open AccessSUMMIT: An integrative approach for better transcriptomic data imputation improves causal gene identification
Genes with moderate-low expression heritability cannot be sufficiently captured with conventional TWAS. This study introduces a new method, Summary-level Unified Method for Modeling Integrated Transcriptome (SUMMIT), to improve the expression prediction of TWAS by using eQTL summary-level data.
- Zichen Zhang
- , Ye Eun Bae
- & Chong Wu
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| Open AccessTranscriptome-wide and stratified genomic structural equation modeling identify neurobiological pathways shared across diverse cognitive traits
High genetic overlap across traits requires methods that can be used to disentangle shared and unique biological pathways. Here, the authors introduce TSEM, a multivariate method for examining tissue-specific gene expression, and apply it to identify genes associated with cognitive traits.
- Andrew D. Grotzinger
- , Javier de la Fuente
- & Elliot M. Tucker-Drob
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Article
| Open AccessSublinear scaling of the cellular proteome with ploidy
Increasing the number of chromosome sets alters the physiology of cells. Here, the authors show that although the number of chromosome sets increases, the proteome does not scale linearly with the increasing ploidy.
- G. Yahya
- , P. Menges
- & Z. Storchova
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Article
| Open AccessProteome effects of genome-wide single gene perturbations
Protein abundance is controlled at the transcriptional, translational and posttranslational levels. Here, Öztürk et al. determine proteome changes resulting from individual knockout of 3308 nonessential genes in the yeast S. pombe, infer gene functionality, and show that protein upregulation under stable transcript expression utilizes optimal codons.
- Merve Öztürk
- , Anja Freiwald
- & Falk Butter
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| Open AccessAlignment of single-cell trajectory trees with CAPITAL
Global alignment of complex cell state trajectories between single-cell datasets remains challenging. Here, the authors present a computational method called CAPITAL to compare branching trajectories, and demonstrate that this method achieves accurate and robust alignments.
- Reiichi Sugihara
- , Yuki Kato
- & Yukio Kawahara
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| Open AccessAllele-specific differential regulation of monoallelically expressed autosomal genes in the cardiac lineage
The authors use allele-specific single cell transcriptomic analysis to elucidate the establishment of monoallelic gene expression in the cardiac lineage. The findings emphasize the importance of allele-specific insight into gene regulation in development, homeostasis and disease.
- Gayan I. Balasooriya
- & David L. Spector
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| Open AccessTissue-specific impacts of aging and genetics on gene expression patterns in humans
Age is a risk factor for many diseases, but the impact of aging on molecular phenotypes is not fully understood. Here, the authors quantify the relative contributions of genetics and aging to gene expression patterns across 27 tissues in humans, showing that age and genetics each play distinct roles in shaping expression phenotypes.
- Ryo Yamamoto
- , Ryan Chung
- & Peter H. Sudmant
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Article
| Open AccessMulti-context genetic modeling of transcriptional regulation resolves novel disease loci
Transcriptome-wide association studies (TWAS) often ignore the specificity and sharing of effects across contexts (e.g., tissues). Here, the authors describe a method to split genetic effects into context-shared and context-specific terms. They apply their method to tissue and single-cell RNA-seq and show improved power in TWAS.
- Mike Thompson
- , Mary Grace Gordon
- & Noah Zaitlen
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Article
| Open AccessIntegrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
Relapsed pediatric acute myeloid leukemia is associated with poor prognosis. Here, the authors use RNA-seq data from 1503 primary samples to create a combined transcriptional and cytomolecular signature to improve relapse risk prediction.
- Benjamin J. Huang
- , Jenny L. Smith
- & Soheil Meshinchi
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Article
| Open AccessMultiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila
Here the authors applied their recently developed multiplexed DNA-FISH Hi-M method to dissect the sources of heterogeneity in topologically associating domain (TAD)-like organization during Drosophila embryogenesis. This single-nucleus analysis allows them to reveal that multiple parameters contribute to shaping the trace of the chromatin path from a single nucleus.
- Markus Götz
- , Olivier Messina
- & Marcelo Nollmann
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Article
| Open AccessRegulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1
LSD1 inhibition blocks the neuroendocrine phenotype of some small cell lung cancers (SCLCs). Here, a genome-wide CRISPR/Cas9 LSD1 inhibitor resistance screen identifies the mRNA-binding protein ZFP36L1 as a gene repressed by LSD1 that when restored inhibits SCLC neuroendocrine differentiation.
- Hsiao-Yun Chen
- , Yavuz T. Durmaz
- & Matthew G. Oser
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Article
| Open AccessSplicing QTL analysis focusing on coding sequences reveals mechanisms for disease susceptibility loci
Splicing QTL (sQTL), genetic variants regulating alternative splicing, can be biologically important, but complex to detect and interpret. Here, the authors identify sQTL by focusing on protein coding sequences, as an alternative to junction-based approaches.
- Kensuke Yamaguchi
- , Kazuyoshi Ishigaki
- & Yuta Kochi
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| Open AccessThe whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force
Genetic mechanisms influencing COVID-19 susceptibility are not well understood. Here, the authors analyzed whole blood RNA-seq data of 465 Japanese individuals with COVID-19, highlighting thousands of fine-mapped variants affecting expression and splicing of genes, as well as the presence of COVID-19 severity-interaction eQTLs.
- Qingbo S. Wang
- , Ryuya Edahiro
- & Yukinori Okada
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| Open AccessExpression plasticity regulates intraspecific variation in the acclimatization potential of a reef-building coral
Phenotypic plasticity is an important response for organisms experiencing climate change. Here, Drury et al. show that stress-hardening can produce durable improvements in coral thermal tolerance, masking substantial variation between individuals.
- Crawford Drury
- , Jenna Dilworth
- & Justin B. Greer
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Article
| Open AccessTranscriptomic diversity in human medullary thymic epithelial cells
The thymus generates all T cells, including those that underly autoimmune diseases. Here, using deep sequencing, the authors profile human medullary thymic epithelial cells and establish a web portal to query their transcriptome, which may serve as a tool to help identify the drivers of autoimmunity.
- Jason A. Carter
- , Léonie Strömich
- & Hannah V. Meyer
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Article
| Open AccessKnowledge-graph-based cell-cell communication inference for spatially resolved transcriptomic data with SpaTalk
Cell-cell communication is a vital feature involving numerous biological processes. Here, the authors develop SpaTalk, a cell-cell communication inference method using knowledge graph for spatially resolved transcriptomic data, providing valuable insights into spatial intercellular tissue dynamics.
- Xin Shao
- , Chengyu Li
- & Xiaohui Fan
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Article
| Open AccessAggregative trans-eQTL analysis detects trait-specific target gene sets in whole blood
Large-scale genetic association studies have identified many trait-associated variants that influence gene expression. Here, the authors present ARCHIE, a tool for identifying sets of genes whose regulation may be related to specific complex traits.
- Diptavo Dutta
- , Yuan He
- & Nilanjan Chatterjee
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Article
| Open AccessBromodomain factor 5 is an essential regulator of transcription in Leishmania
Leishmania use large (5–10 kb) transcriptional start regions, where the chromatin is highly enriched for acetylated histones, to drive the expression of polycistronic gene arrays. Here the authors show bromodomain-containing protein BDF5 is enriched at transcriptional start sites and its depletion leads to cell death in vitro and in murine infections, and they identify its interactors.
- Nathaniel G. Jones
- , Vincent Geoghegan
- & Jeremy C. Mottram
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Article
| Open AccessSenescent cells limit p53 activity via multiple mechanisms to remain viable
To develop therapeutics that selectively eliminate pathological senescent cells it is important to understand their survival mechanisms. Here, the authors show that senescent cells manage to survive by keeping p53 activity in check through multiple mechanisms, including inhibitory mechanisms that involve p53 binding to ribonucleases.
- Ines Sturmlechner
- , Chance C. Sine
- & Jan M. van Deursen
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Article
| Open AccessThe 22q11.2 region regulates presynaptic gene-products linked to schizophrenia
How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons.
- Ralda Nehme
- , Olli Pietiläinen
- & Kevin Eggan
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Article
| Open AccessThe impact of species-wide gene expression variation on Caenorhabditis elegans complex traits
Gene expression links genomic variation to organismal trait differences. Here, the authors identify regulatory loci underlying gene expression variation in C. elegans and demonstrate how this variation could impact other complex traits.
- Gaotian Zhang
- , Nicole M. Roberto
- & Erik C. Andersen
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Article
| Open AccessCardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis
Cardiac fibrosis is a hallmark of heart failure. Here the authors use single-cell RNA-sequencing, spatial transcriptomics, and genetic manipulations, to show that Htra3 regulates cardiac fibrosis by keeping fibroblasts quiescent and by degrading TGF-beta.
- Toshiyuki Ko
- , Seitaro Nomura
- & Issei Komuro
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Article
| Open AccessDosage-sensitive miRNAs trigger modulation of gene expression during genomic imbalance in maize
The role of miRNAs in genome imbalance is unclear. Here, the authors show that cis miRNAs in aneuploids present a predominant gene-dosage effect, whereas trans miRNAs trend toward the inverse level by examining global miRNA modulation in haploid and diploid aneuploids with the varied dosage of multiple chromosomal segments in maize.
- Xiaowen Shi
- , Hua Yang
- & James A. Birchler
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Article
| Open AccessRNase H2, mutated in Aicardi‐Goutières syndrome, resolves co-transcriptional R-loops to prevent DNA breaks and inflammation
RnaseH2 is mutated in severe neuro-inflammatory disorder Aicardi‐Goutières syndrome. Here the authors reveal that RNase H2 controls cellular R-loop homeostasis to promote transcription, genome integrity and prevent R-loop-associated inflammation.
- Agnese Cristini
- , Michael Tellier
- & Natalia Gromak
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Article
| Open AccessGut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate
The role of gut microbiota in acute myeloid leukaemia (AML) remains unclear. Here, the authors show disordered gut microbiota and reduced butyrate cause intestinal barrier damage in AML mice, with increased plasma LPS that accelerates AML progression.
- Ruiqing Wang
- , Xinyu Yang
- & Daoxin Ma
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Article
| Open AccessASCL1 activates neuronal stem cell-like lineage programming through remodeling of the chromatin landscape in prostate cancer
Following androgen receptor pathway inhibition prostate cancers can differentiate towards the neuroendocrine lineage. Here, the authors identify epigenetic alterations regulated by ASCL1 and suggest targeting ASCL1 to reverse the neuroendocrine phenotype.
- Shaghayegh Nouruzi
- , Dwaipayan Ganguli
- & Amina Zoubeidi