Cell Genomics

Current approaches to staging chronic liver diseases have limited utility for predicting liver cancer risk. Here, we employed single-nucleus RNA sequencing (snRNA-seq) to characterize the cellular microenvironment of healthy and pre-malignant livers using two distinct mouse models. Downstream analyses unraveled a previously uncharacterized disease-associated hepatocyte (daHep) transcriptional state. These cells were absent in healthy livers but increasingly prevalent as chronic liver disease progressed. Copy number variation (CNV) analysis of microdissected tissue demonstrated that daHep-enriched regions are riddled with structural variants, suggesting these cells represent a pre-malignant intermediary. Integrated analysis of three recent human snRNA-seq datasets confirmed the presence of a similar phenotype in human chronic liver disease and further supported its enhanced mutational burden. Importantly, we show that high daHep levels precede carcinogenesis and predict a higher risk of hepatocellular carcinoma development. These findings may change the way chronic liver disease patients are staged, surveilled, and risk stratified.

Rodrigo Carlessi

Elena Denisenko

Ebru Boslem

Julia Köhn-Gaone

Nathan Main

N Dianah B Abu Bakar

Gayatri D Shirolkar

Matthew Jones

Aaron B Beasley

Daniel Poppe

Benjamin J Dwyer

Connie Jackaman

M Christian Tjiam

Ryan Lister

Michael Karin

Jonathan A Fallowfield

Timothy J Kendall

Stuart J Forbes

Elin S Gray

John K Olynyk

George Yeoh

Alistair R R Forrest

Grant A Ramm

Mark A Febbraio

Janina E E Tirnitz-Parker

Cell genomics

Cell Genom

Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential.

Pancreatic cancer (PC) is the deadliest malignancy due to late diagnosis. Aberrant alterations in the blood proteome might serve as biomarkers to facilitate early detection of PC. We designed a nested case-control study of incident PC based on a prospective cohort of 38,295 elderly Chinese participants with ∼5.7 years' follow-up. Forty matched case-control pairs passed the quality controls for the proximity extension assay of 1,463 serum proteins. With a lenient threshold of p < 0.005, we discovered regenerating family member 1A (REG1A), REG1B, tumor necrosis factor (TNF), and phospholipase A2 group IB (PLA2G1B) in association with incident PC, among which the two REG1 proteins were replicated using the UK Biobank Pharma Proteomics Project, with effect sizes increasing steadily as diagnosis time approaches the baseline. Mendelian randomization analysis further supported the potential causal effects of REG1 proteins on PC. Taken together, circulating REG1A and REG1B are promising biomarkers and potential therapeutic targets for the early detection and prevention of PC.

Jingjing Lyu

Minghui Jiang

Ziwei Zhu

Hongji Wu

Haonan Kang

Xingjie Hao

Shanshan Cheng

Huan Guo

Xia Shen

Tangchun Wu

Jiang Chang

Chaolong Wang

Identification of biomarkers and potential therapeutic targets for pancreatic cancer by proteomic analysis in two prospective cohorts

通过蛋白质组学分析在两个前瞻性队列中鉴定胰腺癌的生物标志物和潜在治疗靶点

Human genetic diversity can reveal critical factors in host-pathogen interactions. This is especially useful for human-restricted pathogens like

Kyle D Gibbs

Liuyang Wang

Zhuo Yang

Caroline E Anderson

Jeffrey S Bourgeois

Yanlu Cao

Margaret R Gaggioli

Martin Biel

Rosa Puertollano

Cheng-Chang Chen

Dennis C Ko

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

影响MCOLN2的人类变异通过镁剥夺限制伤寒沙门氏菌的复制

Fish air breathing is crucial for the transition of vertebrates from water to land. So far, the genes involved in fish air breathing have not been well identified. Here, we performed gene enrichment analysis of positively selected genes (PSGs) in loach (Misgurnus anguillicaudatus, an air-breathing fish) in comparison to Triplophysa tibetana (a non-air-breathing fish), haplotype-resolved genome assembly of the loach, and gene evolutionary analysis of air-breathing and non-air-breathing fishes and found that the PSG mex3a originated from ancient air-breathing fish species. Deletion of Mex3a impaired loach air-breathing capacity by inhibiting angiogenesis through its interaction with T-box transcription factor 20. Mex3a overexpression significantly promoted angiogenesis. Structural analysis and point mutation revealed the critical role of the 201st amino acid in loach Mex3a for angiogenesis. Our findings innovatively indicate that the ancient mex3a is a fish air-breathing gene, which holds significance for understanding fish air breathing and provides a valuable resource for cultivating hypoxia-tolerant fish varieties.

Bing Sun

Qingshan Li

Xinxin Xiao

Jianwei Zhang

Ying Zhou

Yuwei Huang

Jian Gao

Xiaojuan Cao

The loach haplotype-resolved genome and the identification of Mex3a involved in fish air breathing

泥鳅单倍型解析基因组及鱼类空气呼吸相关Mex3a的鉴定

Daiyun Huang

Jia Meng

Kunqi Chen

AI techniques have facilitated the understanding of epitranscriptome distribution

AI技术促进了表观转录组分布的理解

Copy-number variants (CNVs) that increase the risk for neurodevelopmental disorders also affect cognitive ability. However, such CNVs remain challenging to study due to their scarcity, limiting our understanding of gene-dosage-sensitive biological processes linked to cognitive ability. We performed a genome-wide association study (GWAS) in 258,292 individuals, which identified-for the first time-a duplication at 2q12.3 associated with higher cognitive performance. We developed a functional-burden analysis, which tested the association between cognition and CNVs disrupting 6,502 gene sets biologically defined across tissues, cell types, and ontologies. Among those, 864 gene sets were associated with cognition, and effect sizes of deletion and duplication were negatively correlated. The latter suggested that functions across all biological processes were sensitive to either deletions (e.g., subcortical regions, postsynaptic) or duplications (e.g., cerebral cortex, presynaptic). Associations between non-brain tissues and cognition were driven partly by constrained genes, which may shed light on medical comorbidities in neurodevelopmental disorders.

Guillaume Huguet

Thomas Renne

Cécile Poulain

Alma Dubuc

Kuldeep Kumar

Sayeh Kazem

Worrawat Engchuan

Omar Shanta

Elise Douard

Catherine Proulx

Martineau Jean-Louis

Zohra Saci

Josephine Mollon

Laura M Schultz

Emma E M Knowles

Simon R Cox

David Porteous

Gail Davies

Paul Redmond

Sarah E Harris

Gunter Schumann

Guillaume Dumas

Aurélie Labbe

Zdenka Pausova

Tomas Paus

Stephen W Scherer

Jonathan Sebat

Laura Almasy

David C Glahn

Sébastien Jacquemont

Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

基因剂量对认知能力的影响：基于功能的关联研究跨越脑与非脑过程

Understanding the rapidly evolving landscape of single-cell and spatial omic technologies is crucial for advancing biomedical research and drug development. We provide a living review of both mature and emerging commercial platforms, highlighting key methodologies and trends shaping the field. This review spans from foundational single-cell technologies such as microfluidics and plate-based methods to newer approaches like combinatorial indexing; on the spatial side, we consider next-generation sequencing and imaging-based spatial transcriptomics. Finally, we highlight emerging methodologies that may fundamentally expand the scope for data generation within pharmaceutical research, creating opportunities to discover and validate novel drug mechanisms. Overall, this review serves as a critical resource for navigating the commercialization and application of single-cell and spatial omic technologies in pharmaceutical and academic research.

Joachim De Jonghe

James W Opzoomer

Amaia Vilas-Zornoza

Benedikt S Nilges

Peter Crane

Marco Vicari

Hower Lee

David Lara-Astiaso

Torsten Gross

Jörg Morf

Kim Schneider

Juliana Cudini

Lorenzo Ramos-Mucci

Dylan Mooijman

Katarína Tiklová

Sergio Marco Salas

Christoffer Mattsson Langseth

Nachiket D Kashikar

Denis Schapiro

Joakim Lundeberg

Mats Nilsson

Alex K Shalek

Adam P Cribbs

Jake P Taylor-King

scTrends: A living review of commercial single-cell and spatial 'omic technologies

scTrends：商业单细胞和空间组学技术的动态综述

Gene expression in individual neurons can change during development to adulthood and can have large effects on behavior. Additionally, the insulin/insulin-like signaling (IIS) pathway regulates many of the adult functions of Caenorhabditis elegans, including learning and memory, via transcriptional changes. We used the deep resolution of single-nucleus RNA sequencing to define the adult transcriptome of each neuron in wild-type and daf-2 mutants, revealing expression differences between L4 larval and adult neurons in chemoreceptors, synaptic genes, and learning/memory genes. We used these data to identify adult new AWC-specific regulators of chemosensory function that emerge upon adulthood. daf-2 gene expression changes correlate with improved cognitive functions, particularly in the AWC sensory neuron that controls learning and associative memory; behavioral assays of AWC-specific daf-2 genes revealed their roles in cognitive function. Combining technology and functional validation, we identified conserved genes that function in specific adult neurons to control behavior, including learning and memory.

Jonathan St Ange

Yifei Weng

Rachel Kaletsky

Morgan E Stevenson

Rebecca S Moore

Shiyi Zhou

Coleen T Murphy

Adult single-nucleus neuronal transcriptomes of insulin signaling mutants reveal regulators of behavior and learning

胰岛素信号通路突变体成年单核神经元转录组揭示行为和学习调控因子

Identifying the molecular effects of human genetic variation across cellular contexts is crucial for understanding the mechanisms underlying disease-associated loci, yet many cell types and developmental stages remain underexplored. Here, we harnessed the potential of heterogeneous differentiating cultures (HDCs), an in vitro system in which pluripotent cells asynchronously differentiate into a broad spectrum of cell types. We generated HDCs for 53 human donors and collected single-cell RNA sequencing data from over 900,000 cells. We identified expression quantitative trait loci in 29 cell types and characterized regulatory dynamics across diverse differentiation trajectories. This revealed novel regulatory variants for genes involved in key developmental and disease-related processes while replicating known effects from primary tissues and dynamic regulatory effects associated with a range of complex traits.

Joshua M Popp

Katherine Rhodes

Radhika Jangi

Mingyuan Li

Kenneth Barr

Karl Tayeb

Alexis Battle

Yoav Gilad

Cell type and dynamic state govern genetic regulation of gene expression in heterogeneous differentiating cultures

细胞类型和动态状态调控异质性分化培养物中基因表达的遗传调控

短名	Cell. Genom.
Journal Impact	11.10
国际分区	GENETICS & HEREDITY(Q1)

ISSN	2666-979X
h-index	20

涉及主题	geneticsgenomicsgenome technologyhuman geneticscancer genomicsprecision medicine
出版信息	出版商: Cell Press，出版周期: ，期刊类型: journal，开源期刊: 是
基本数据	创刊年份: 2021，原创研究文献占比: ，自引率:， Gold OA占比:
期刊费用	$8900详情
平均审稿周期	21 weeks

Cell Genomics

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Single-nucleus RNA sequencing of pre-malignant liver reveals disease-associated hepatocyte state with HCC prognostic potential.

Identification of biomarkers and potential therapeutic targets for pancreatic cancer by proteomic analysis in two prospective cohorts

Human variation impacting MCOLN2 restricts Salmonella Typhi replication by magnesium deprivation

The loach haplotype-resolved genome and the identification of Mex3a involved in fish air breathing

AI techniques have facilitated the understanding of epitranscriptome distribution

AI techniques have facilitated the understanding of epitranscriptome distribution

Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes

scTrends: A living review of commercial single-cell and spatial 'omic technologies

Adult single-nucleus neuronal transcriptomes of insulin signaling mutants reveal regulators of behavior and learning

Cell type and dynamic state govern genetic regulation of gene expression in heterogeneous differentiating cultures