Pub Date : 2024-06-12Epub Date: 2024-05-23DOI: 10.1016/j.xgen.2024.100566
H Nayanga Thirimanne, Damian Almiron-Bonnin, Nicholas Nuechterlein, Sonali Arora, Matt Jensen, Carolina A Parada, Chengxiang Qiu, Frank Szulzewsky, Collin W English, William C Chen, Philipp Sievers, Farshad Nassiri, Justin Z Wang, Tiemo J Klisch, Kenneth D Aldape, Akash J Patel, Patrick J Cimino, Gelareh Zadeh, Felix Sahm, David R Raleigh, Jay Shendure, Manuel Ferreira, Eric C Holland
Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.
{"title":"Meningioma transcriptomic landscape demonstrates novel subtypes with regional associated biology and patient outcome.","authors":"H Nayanga Thirimanne, Damian Almiron-Bonnin, Nicholas Nuechterlein, Sonali Arora, Matt Jensen, Carolina A Parada, Chengxiang Qiu, Frank Szulzewsky, Collin W English, William C Chen, Philipp Sievers, Farshad Nassiri, Justin Z Wang, Tiemo J Klisch, Kenneth D Aldape, Akash J Patel, Patrick J Cimino, Gelareh Zadeh, Felix Sahm, David R Raleigh, Jay Shendure, Manuel Ferreira, Eric C Holland","doi":"10.1016/j.xgen.2024.100566","DOIUrl":"10.1016/j.xgen.2024.100566","url":null,"abstract":"<p><p>Meningiomas, although mostly benign, can be recurrent and fatal. World Health Organization (WHO) grading of the tumor does not always identify high-risk meningioma, and better characterizations of their aggressive biology are needed. To approach this problem, we combined 13 bulk RNA sequencing (RNA-seq) datasets to create a dimension-reduced reference landscape of 1,298 meningiomas. The clinical and genomic metadata effectively correlated with landscape regions, which led to the identification of meningioma subtypes with specific biological signatures. The time to recurrence also correlated with the map location. Further, we developed an algorithm that maps new patients onto this landscape, where the nearest neighbors predict outcome. This study highlights the utility of combining bulk transcriptomic datasets to visualize the complexity of tumor populations. Further, we provide an interactive tool for understanding the disease and predicting patient outcomes. This resource is accessible via the online tool Oncoscape, where the scientific community can explore the meningioma landscape.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228955/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141094730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-12DOI: 10.1016/j.xgen.2024.100584
Francisco Aya, Juan Valcárcel
Alternative splicing contributes to shaping lineage-specific gene expression and phenotypes. In this issue of Cell Genomics, Recinos, Bao, Wang, et al.1 report that the balance between splicing isoforms of the microtubule-associated protein Tau in the brain is differentially regulated among primates by the RNA-binding protein MBNL2, with consequences for protein aggregation and neurodegeneration in humans.
替代剪接有助于形成特定品系的基因表达和表型。在本期《细胞基因组学》(Cell Genomics)杂志上,Recinos、Bao、Wang 等人1 报告说,大脑中微管相关蛋白 Tau 的剪接异构体之间的平衡在灵长类动物中受到 RNA 结合蛋白 MBNL2 的不同调控,从而对人类的蛋白聚集和神经退行性变产生影响。
{"title":"Shaping human brain development and vulnerability through alternative splicing.","authors":"Francisco Aya, Juan Valcárcel","doi":"10.1016/j.xgen.2024.100584","DOIUrl":"10.1016/j.xgen.2024.100584","url":null,"abstract":"<p><p>Alternative splicing contributes to shaping lineage-specific gene expression and phenotypes. In this issue of Cell Genomics, Recinos, Bao, Wang, et al.<sup>1</sup> report that the balance between splicing isoforms of the microtubule-associated protein Tau in the brain is differentially regulated among primates by the RNA-binding protein MBNL2, with consequences for protein aggregation and neurodegeneration in humans.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141319154","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-12Epub Date: 2024-05-01DOI: 10.1016/j.xgen.2023.100421
Venugopalan D Nair, Hanna Pincas, Gregory R Smith, Elena Zaslavsky, Yongchao Ge, Mary Anne S Amper, Mital Vasoya, Maria Chikina, Yifei Sun, Archana Natarajan Raja, Weiguang Mao, Nicole R Gay, Karyn A Esser, Kevin S Smith, Bingqing Zhao, Laurens Wiel, Aditya Singh, Malene E Lindholm, David Amar, Stephen Montgomery, Michael P Snyder, Martin J Walsh, Stuart C Sealfon
Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.
经常锻炼对身体和大脑健康有很多益处,但人们对介导各组织锻炼效果的分子机制仍然知之甚少。在这里,我们分析了来自对照组和耐力运动训练(EET)大鼠八个组织的 400 个高质量 DNA 甲基化、ATAC-seq 和 RNA-seq 数据集。通过整合基线数据集,绘制了表观遗传控制特征的基因位置依赖性图谱,并确定了各组织中不同的调控景观。各组织对 8 周 EET 的转录反应几乎没有重叠,主要由组织类型丰富的基因组成。我们发现 EET 诱导的转录组和表观基因组变化存在性别差异。然而,性别差异基因反应与共同的信号通路有关。我们发现,许多 G 蛋白偶联受体编码基因受到 EET 的调控,这表明这些受体在介导不同组织对训练的分子适应方面发挥了作用。我们的研究结果为EET诱导跨器官健康益处的机制提供了新的见解。
{"title":"Molecular adaptations in response to exercise training are associated with tissue-specific transcriptomic and epigenomic signatures.","authors":"Venugopalan D Nair, Hanna Pincas, Gregory R Smith, Elena Zaslavsky, Yongchao Ge, Mary Anne S Amper, Mital Vasoya, Maria Chikina, Yifei Sun, Archana Natarajan Raja, Weiguang Mao, Nicole R Gay, Karyn A Esser, Kevin S Smith, Bingqing Zhao, Laurens Wiel, Aditya Singh, Malene E Lindholm, David Amar, Stephen Montgomery, Michael P Snyder, Martin J Walsh, Stuart C Sealfon","doi":"10.1016/j.xgen.2023.100421","DOIUrl":"10.1016/j.xgen.2023.100421","url":null,"abstract":"<p><p>Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":11.1,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140863863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08Epub Date: 2024-05-01DOI: 10.1016/j.xgen.2024.100545
Patrick B Chen, Rachel Chen, Nathan LaPierre, Zeyuan Chen, Joel Mefford, Emilie Marcus, Matthew G Heffel, Daniela C Soto, Jason Ernst, Chongyuan Luo, Jonathan Flint
Knowing the genes involved in quantitative traits provides an entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six quantitative trait loci (QTLs) by quantitative complementation, and identified six genes. Four genes, Lamp, Ptprd, Nptx2, and Sh3gl, have known roles in synapse function; the fifth, Psip1, was not previously implicated in behavior; and the sixth is a long non-coding RNA, 4933413L06Rik, of unknown function. Variation in transcriptome and epigenetic modalities occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results relieve a bottleneck in using genetic mapping of QTLs to uncover biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.
{"title":"Complementation testing identifies genes mediating effects at quantitative trait loci underlying fear-related behavior.","authors":"Patrick B Chen, Rachel Chen, Nathan LaPierre, Zeyuan Chen, Joel Mefford, Emilie Marcus, Matthew G Heffel, Daniela C Soto, Jason Ernst, Chongyuan Luo, Jonathan Flint","doi":"10.1016/j.xgen.2024.100545","DOIUrl":"10.1016/j.xgen.2024.100545","url":null,"abstract":"<p><p>Knowing the genes involved in quantitative traits provides an entry point to understanding the biological bases of behavior, but there are very few examples where the pathway from genetic locus to behavioral change is known. To explore the role of specific genes in fear behavior, we mapped three fear-related traits, tested fourteen genes at six quantitative trait loci (QTLs) by quantitative complementation, and identified six genes. Four genes, Lamp, Ptprd, Nptx2, and Sh3gl, have known roles in synapse function; the fifth, Psip1, was not previously implicated in behavior; and the sixth is a long non-coding RNA, 4933413L06Rik, of unknown function. Variation in transcriptome and epigenetic modalities occurred preferentially in excitatory neurons, suggesting that genetic variation is more permissible in excitatory than inhibitory neuronal circuits. Our results relieve a bottleneck in using genetic mapping of QTLs to uncover biology underlying behavior and prompt a reconsideration of expected relationships between genetic and functional variation.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140860711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1016/j.xgen.2024.100557
Chakit Arora, Marin Matic, Luisa Bisceglia, Pierluigi Di Chiaro, Natalia De Oliveira Rosa, Francesco Carli, Lauren Clubb, Lorenzo Amir Nemati Fard, Giorgos Kargas, Giuseppe R Diaferia, Ranka Vukotic, Luana Licata, Guanming Wu, Gioacchino Natoli, J Silvio Gutkind, Francesco Raimondi
We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many involving receptor-biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens, which we further validated. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it).
我们探索了癌症转录组学数据集中 G 蛋白偶联受体(GPCR)配体系统的失调,以发现肿瘤学中新的治疗机会。我们得出了受体与配体及其生物合成酶的相互作用网络。在不同的癌症亚型中,多种 GPCR 与其上游伙伴一起受到不同的调控,并与特定的转录程序和患者生存模式相关联。受体配体(或酶)伙伴的表达改善了患者分层,这表明 GPCR 网络的激活在调节癌症表型方面发挥着协同作用。值得注意的是,我们在几种癌症分子亚型中发现了许多这样的轴,包括许多涉及神经递质受体生物合成酶的轴。我们发现,在大规模癌细胞药物筛选中,来自这些可作用轴的 GPCR(包括毒蕈碱、腺苷、5-羟色胺和趋化因子受体等)是多种药物的靶点,这些药物具有抗生长作用,我们对这些靶点进行了进一步验证。我们通过一个网络应用程序(gpcrcanceraxes.bioinfolab.sns.it)免费提供了这项研究产生的结果。
{"title":"The landscape of cancer-rewired GPCR signaling axes.","authors":"Chakit Arora, Marin Matic, Luisa Bisceglia, Pierluigi Di Chiaro, Natalia De Oliveira Rosa, Francesco Carli, Lauren Clubb, Lorenzo Amir Nemati Fard, Giorgos Kargas, Giuseppe R Diaferia, Ranka Vukotic, Luana Licata, Guanming Wu, Gioacchino Natoli, J Silvio Gutkind, Francesco Raimondi","doi":"10.1016/j.xgen.2024.100557","DOIUrl":"10.1016/j.xgen.2024.100557","url":null,"abstract":"<p><p>We explored the dysregulation of G-protein-coupled receptor (GPCR) ligand systems in cancer transcriptomics datasets to uncover new therapeutics opportunities in oncology. We derived an interaction network of receptors with ligands and their biosynthetic enzymes. Multiple GPCRs are differentially regulated together with their upstream partners across cancer subtypes and are associated to specific transcriptional programs and to patient survival patterns. The expression of both receptor-ligand (or enzymes) partners improved patient stratification, suggesting a synergistic role for the activation of GPCR networks in modulating cancer phenotypes. Remarkably, we identified many such axes across several cancer molecular subtypes, including many involving receptor-biosynthetic enzymes for neurotransmitters. We found that GPCRs from these actionable axes, including, e.g., muscarinic, adenosine, 5-hydroxytryptamine, and chemokine receptors, are the targets of multiple drugs displaying anti-growth effects in large-scale, cancer cell drug screens, which we further validated. We have made the results generated in this study freely available through a webapp (gpcrcanceraxes.bioinfolab.sns.it).</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1016/j.xgen.2024.100560
Balaji Santhanam, Madison Sluter, M Madan Babu
GPCR signaling can contribute to establishing the tumor microenvironment and influence the progression and metabolism of tumors. Arora et al.1 describe a systems-level approach to investigate the patterns of co-expression of GPCR signaling pathway networks across diverse tumors and identify network components that correlate with patient-survival data across different cancer types.
{"title":"Exploring GPCR signaling pathway networks as cancer therapeutic targets.","authors":"Balaji Santhanam, Madison Sluter, M Madan Babu","doi":"10.1016/j.xgen.2024.100560","DOIUrl":"10.1016/j.xgen.2024.100560","url":null,"abstract":"<p><p>GPCR signaling can contribute to establishing the tumor microenvironment and influence the progression and metabolism of tumors. Arora et al.<sup>1</sup> describe a systems-level approach to investigate the patterns of co-expression of GPCR signaling pathway networks across diverse tumors and identify network components that correlate with patient-survival data across different cancer types.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08Epub Date: 2024-04-24DOI: 10.1016/j.xgen.2024.100542
Matthew Ginley-Hidinger, Hosiana Abewe, Kyle Osborne, Alexandra Richey, Noel Kitchen, Katelyn L Mortenson, Erin M Wissink, John Lis, Xiaoyang Zhang, Jason Gertz
Cis-regulatory elements control transcription levels, temporal dynamics, and cell-cell variation or transcriptional noise. However, the combination of regulatory features that control these different attributes is not fully understood. Here, we used single-cell RNA-seq during an estrogen treatment time course and machine learning to identify predictors of expression timing and noise. We found that genes with multiple active enhancers exhibit faster temporal responses. We verified this finding by showing that manipulation of enhancer activity changes the temporal response of estrogen target genes. Analysis of transcriptional noise uncovered a relationship between promoter and enhancer activity, with active promoters associated with low noise and active enhancers linked to high noise. Finally, we observed that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise. Overall, our results indicate a fundamental tradeoff between a gene's ability to quickly respond to incoming signals and maintain low variation across cells.
{"title":"Cis-regulatory control of transcriptional timing and noise in response to estrogen.","authors":"Matthew Ginley-Hidinger, Hosiana Abewe, Kyle Osborne, Alexandra Richey, Noel Kitchen, Katelyn L Mortenson, Erin M Wissink, John Lis, Xiaoyang Zhang, Jason Gertz","doi":"10.1016/j.xgen.2024.100542","DOIUrl":"10.1016/j.xgen.2024.100542","url":null,"abstract":"<p><p>Cis-regulatory elements control transcription levels, temporal dynamics, and cell-cell variation or transcriptional noise. However, the combination of regulatory features that control these different attributes is not fully understood. Here, we used single-cell RNA-seq during an estrogen treatment time course and machine learning to identify predictors of expression timing and noise. We found that genes with multiple active enhancers exhibit faster temporal responses. We verified this finding by showing that manipulation of enhancer activity changes the temporal response of estrogen target genes. Analysis of transcriptional noise uncovered a relationship between promoter and enhancer activity, with active promoters associated with low noise and active enhancers linked to high noise. Finally, we observed that co-expression across single cells is an emergent property associated with chromatin looping, timing, and noise. Overall, our results indicate a fundamental tradeoff between a gene's ability to quickly respond to incoming signals and maintain low variation across cells.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099348/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140871645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08Epub Date: 2024-04-30DOI: 10.1016/j.xgen.2024.100544
Robert F Hillary, Hong Kiat Ng, Daniel L McCartney, Hannah R Elliott, Rosie M Walker, Archie Campbell, Felicia Huang, Kenan Direk, Paul Welsh, Naveed Sattar, Janie Corley, Caroline Hayward, Andrew M McIntosh, Cathie Sudlow, Kathryn L Evans, Simon R Cox, John C Chambers, Marie Loh, Caroline L Relton, Riccardo E Marioni, Paul D Yousefi, Matthew Suderman
Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.
{"title":"Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.","authors":"Robert F Hillary, Hong Kiat Ng, Daniel L McCartney, Hannah R Elliott, Rosie M Walker, Archie Campbell, Felicia Huang, Kenan Direk, Paul Welsh, Naveed Sattar, Janie Corley, Caroline Hayward, Andrew M McIntosh, Cathie Sudlow, Kathryn L Evans, Simon R Cox, John C Chambers, Marie Loh, Caroline L Relton, Riccardo E Marioni, Paul D Yousefi, Matthew Suderman","doi":"10.1016/j.xgen.2024.100544","DOIUrl":"10.1016/j.xgen.2024.100544","url":null,"abstract":"<p><p>Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N = 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099341/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140869007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-08DOI: 10.1016/j.xgen.2024.100558
Yin Wang, Ying Wai Chan
In this issue of Cell Genomics, Wang, Liu, Zuo, Wang, et al.1 investigate rare variants in hepatocellular carcinoma (HCC) by performing the first rare-variant association study (RVAS) in a Chinese population cohort. It uncovers BRCAness phenotypes associated with the NRDE2-p.N377I variant, suggesting PARP inhibitors as a promising therapeutic approach for certain HCC patients.
{"title":"Rare-variant association study unveils the Achilles' heel for HCC.","authors":"Yin Wang, Ying Wai Chan","doi":"10.1016/j.xgen.2024.100558","DOIUrl":"10.1016/j.xgen.2024.100558","url":null,"abstract":"<p><p>In this issue of Cell Genomics, Wang, Liu, Zuo, Wang, et al.<sup>1</sup> investigate rare variants in hepatocellular carcinoma (HCC) by performing the first rare-variant association study (RVAS) in a Chinese population cohort. It uncovers BRCAness phenotypes associated with the NRDE2-p.N377I variant, suggesting PARP inhibitors as a promising therapeutic approach for certain HCC patients.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140900696","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The complex pathobiology of late-onset Alzheimer's disease (AD) poses significant challenges to therapeutic and preventative interventions. Despite these difficulties, genomics and related disciplines are allowing fundamental mechanistic insights to emerge with clarity, particularly with the introduction of high-resolution sequencing technologies. After all, the disrupted processes at the interface between DNA and gene expression, which we call the broken AD genome, offer detailed quantitative evidence unrestrained by preconceived notions about the disease. In addition to highlighting biological pathways beyond the classical pathology hallmarks, these advances have revitalized drug discovery efforts and are driving improvements in clinical tools. We review genetic, epigenomic, and gene expression findings related to AD pathogenesis and explore how their integration enables a better understanding of the multicellular imbalances contributing to this heterogeneous condition. The frontiers opening on the back of these research milestones promise a future of AD care that is both more personalized and predictive.
晚发性阿尔茨海默病(AD)的病理生物学非常复杂,给治疗和预防干预带来了巨大挑战。尽管存在这些困难,但基因组学和相关学科,尤其是高分辨率测序技术的引入,使基本的机理认识得以清晰呈现。毕竟,DNA 与基因表达界面的中断过程(我们称之为 "破碎的 AD 基因组")提供了详细的定量证据,不受对该疾病先入为主的观念的限制。除了强调经典病理学特征之外的生物学途径之外,这些进展还为药物发现工作注入了新的活力,并推动了临床工具的改进。我们回顾了与多发性硬化症发病机制相关的遗传学、表观基因组学和基因表达研究成果,并探讨了如何通过整合这些研究成果更好地理解导致这种异质性疾病的多细胞失衡。这些具有里程碑意义的研究成果所开辟的前沿领域有望为未来的注意力缺失症治疗提供更加个性化和更具预测性的服务。
{"title":"The broken Alzheimer's disease genome.","authors":"Cláudio Gouveia Roque, Hemali Phatnani, Ulrich Hengst","doi":"10.1016/j.xgen.2024.100555","DOIUrl":"10.1016/j.xgen.2024.100555","url":null,"abstract":"<p><p>The complex pathobiology of late-onset Alzheimer's disease (AD) poses significant challenges to therapeutic and preventative interventions. Despite these difficulties, genomics and related disciplines are allowing fundamental mechanistic insights to emerge with clarity, particularly with the introduction of high-resolution sequencing technologies. After all, the disrupted processes at the interface between DNA and gene expression, which we call the broken AD genome, offer detailed quantitative evidence unrestrained by preconceived notions about the disease. In addition to highlighting biological pathways beyond the classical pathology hallmarks, these advances have revitalized drug discovery efforts and are driving improvements in clinical tools. We review genetic, epigenomic, and gene expression findings related to AD pathogenesis and explore how their integration enables a better understanding of the multicellular imbalances contributing to this heterogeneous condition. The frontiers opening on the back of these research milestones promise a future of AD care that is both more personalized and predictive.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11099344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140854556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}