Cell genomics最新文献_第2页

Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage. 迁移学习揭示了转录因子剂量定量反应的序列决定因素。

IF 11.1

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-02-27 DOI: 10.1016/j.xgen.2025.100780

Sahin Naqvi, Seungsoo Kim, Saman Tabatabaee, Anusri Pampari, Anshul Kundaje, Jonathan K Pritchard, Joanna Wysocka

{"title":"Transfer learning reveals sequence determinants of the quantitative response to transcription factor dosage.","authors":"Sahin Naqvi, Seungsoo Kim, Saman Tabatabaee, Anusri Pampari, Anshul Kundaje, Jonathan K Pritchard, Joanna Wysocka","doi":"10.1016/j.xgen.2025.100780","DOIUrl":"10.1016/j.xgen.2025.100780","url":null,"abstract":"Deep learning models have advanced our ability to predict cell-type-specific chromatin patterns from transcription factor (TF) binding motifs, but their application to perturbed contexts remains limited. We applied transfer learning to predict how concentrations of the dosage-sensitive TFs TWIST1 and SOX9 affect regulatory element (RE) chromatin accessibility in facial progenitor cells, achieving near-experimental accuracy. High-affinity motifs that allow for heterotypic TF co-binding and are concentrated at the center of REs buffer against quantitative changes in TF dosage and predict unperturbed accessibility. Conversely, low-affinity or homotypic binding motifs distributed throughout REs drive sensitive responses with minimal impact on unperturbed accessibility. Both buffering and sensitizing features display purifying selection signatures. We validated these sequence features through reporter assays and demonstrated that TF-nucleosome competition can explain low-affinity motifs' sensitizing effects. This combination of transfer learning and quantitative chromatin response measurements provides a novel approach for uncovering additional layers of the cis-regulatory code.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100780"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143532108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distance matters: How protein regulators facilitate enhancer-promoter interactions and transcription.

IF 11.1

Cell genomics Pub Date : 2025-03-12 DOI: 10.1016/j.xgen.2025.100817

Masahiro Nagano, Anders S Hansen

引用次数: 0

Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM.

IF 11.1

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-03-04 DOI: 10.1016/j.xgen.2025.100784

Hung-Hsin Chen, Heather M Highland, Elizabeth G Frankel, Alyssa C Scartozzi, Xinruo Zhang, Rashedeh Roshani, Priya Sharma, Asha Kar, Victoria L Buchanan, Hannah G Polikowsky, Lauren E Petty, Jungkyun Seo, Mohammad Yaser Anwar, Daeeun Kim, Mariaelisa Graff, Kristin L Young, Wanying Zhu, Kalypso Karastergiou, Douglas M Shaw, Anne E Justice, Lindsay Fernández-Rhodes, Mohanraj Krishnan, Absalon Gutierrez, Peter J McCormick, Carlos A Aguilar-Salinas, Maria Teresa Tusié-Luna, Linda Liliana Muñoz-Hernandez, Miguel Herrera-Hernandez, Miryoung Lee, Eric R Gamazon, Nancy J Cox, Päivi Pajukanta, Susan K Fried, Penny Gordon-Larsen, Ravi V Shah, Susan P Fisher-Hoch, Joseph B McCormick, Kari E North, Jennifer E Below

{"title":"Multiomics reveal key inflammatory drivers of severe obesity: IL4R, LILRA5, and OSM.","authors":"Hung-Hsin Chen, Heather M Highland, Elizabeth G Frankel, Alyssa C Scartozzi, Xinruo Zhang, Rashedeh Roshani, Priya Sharma, Asha Kar, Victoria L Buchanan, Hannah G Polikowsky, Lauren E Petty, Jungkyun Seo, Mohammad Yaser Anwar, Daeeun Kim, Mariaelisa Graff, Kristin L Young, Wanying Zhu, Kalypso Karastergiou, Douglas M Shaw, Anne E Justice, Lindsay Fernández-Rhodes, Mohanraj Krishnan, Absalon Gutierrez, Peter J McCormick, Carlos A Aguilar-Salinas, Maria Teresa Tusié-Luna, Linda Liliana Muñoz-Hernandez, Miguel Herrera-Hernandez, Miryoung Lee, Eric R Gamazon, Nancy J Cox, Päivi Pajukanta, Susan K Fried, Penny Gordon-Larsen, Ravi V Shah, Susan P Fisher-Hoch, Joseph B McCormick, Kari E North, Jennifer E Below","doi":"10.1016/j.xgen.2025.100784","DOIUrl":"10.1016/j.xgen.2025.100784","url":null,"abstract":"Polygenic severe obesity (body mass index [BMI] ≥40 kg/m2) has increased, especially in Hispanic/Latino populations, yet we know little about the underlying mechanistic pathways. We analyzed whole-blood multiomics data to identify genes differentially regulated in severe obesity in Mexican Americans from the Cameron County Hispanic Cohort. Our RNA sequencing analysis identified 124 genes significantly differentially expressed between severe obesity cases (BMI ≥40 kg/m2) and controls (BMI <25 kg/m2); 33% replicated in an independent sample from the same population. Our integrative approach identified inflammatory genes, including IL4R, ZNF438, and LILRA5. Several genes displayed transcriptomic effects on severe obesity in subcutaneous adipose tissue. We further showed that the genetic regulation of these genes is associated with several traits in a large biobank, including bone fractures, obstructive sleep apnea, and hyperaldosteronism, illuminating potential risk mechanisms. Our findings furnish a molecular architecture of the severe obesity phenotype across multiple molecular domains.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100784"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans.

IF 11.1

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-03-04 DOI: 10.1016/j.xgen.2025.100782

Jie Ping, Xinyi Liu, Yiming Lu, Cheng Quan, Pengcheng Fan, Hao Lu, Qi Li, Cuiling Wang, Zheng Zhang, Mengyu Liu, Shunqi Chen, Lingle Chang, Yuqing Jiang, Qilin Huang, Jie Liu, Tana Wuren, Huifang Liu, Ying Hao, Longli Kang, Guanjun Liu, Hui Lu, Xiaojun Wei, Yuting Wang, Yuanfeng Li, Hao Guo, Yongquan Cui, Haoxiang Zhang, Yang Zhang, Yujia Zhai, Yaoxi He, Wangshan Zheng, Xuebin Qi, Ouzhuluobu, Huiping Ma, Linpeng Yang, Xin Wang, Wanjun Jin, Ying Cui, Rili Ge, Shizheng Wu, Yuan Wei, Bing Su, Fuchu He, Hongxing Zhang, Gangqiao Zhou

{"title":"A highland-adaptation variant near MCUR1 reduces its transcription and attenuates erythrogenesis in Tibetans.","authors":"Jie Ping, Xinyi Liu, Yiming Lu, Cheng Quan, Pengcheng Fan, Hao Lu, Qi Li, Cuiling Wang, Zheng Zhang, Mengyu Liu, Shunqi Chen, Lingle Chang, Yuqing Jiang, Qilin Huang, Jie Liu, Tana Wuren, Huifang Liu, Ying Hao, Longli Kang, Guanjun Liu, Hui Lu, Xiaojun Wei, Yuting Wang, Yuanfeng Li, Hao Guo, Yongquan Cui, Haoxiang Zhang, Yang Zhang, Yujia Zhai, Yaoxi He, Wangshan Zheng, Xuebin Qi, Ouzhuluobu, Huiping Ma, Linpeng Yang, Xin Wang, Wanjun Jin, Ying Cui, Rili Ge, Shizheng Wu, Yuan Wei, Bing Su, Fuchu He, Hongxing Zhang, Gangqiao Zhou","doi":"10.1016/j.xgen.2025.100782","DOIUrl":"10.1016/j.xgen.2025.100782","url":null,"abstract":"To identify genomic regions subject to positive selection that might contain genes involved in high-altitude adaptation (HAA), we performed a genome-wide scan by whole-genome sequencing of Tibetan highlanders and Han lowlanders. We revealed a collection of candidate genes located in 30 genomic loci under positive selection. Among them, MCUR1 at 6p23 was a novel pronounced candidate. By single-cell RNA sequencing and comprehensive functional studies, we demonstrated that MCUR1 depletion leads to impairment of erythropoiesis under hypoxia and normoxia. Mechanistically, MCUR1 knockdown reduced mitochondrial Ca2+ uptake and then concomitantly increased cytosolic Ca2+ levels, which thereby reduced erythropoiesis via the CAMKK2-AMPK-mTOR axis. Further, we revealed rs61644582 at 6p23 as an expression quantitative trait locus for MCUR1 and a functional variant that confers an allele-specific transcriptional regulation of MCUR1. Overall, MCUR1-mediated mitochondrial Ca2+ homeostasis is highlighted as a novel regulator of erythropoiesis, deepening our understanding of the genetic mechanism of HAA.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100782"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143569170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-range enhancer-controlled genes are hypersensitive to regulatory factor perturbations.

IF 11.1

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-02-25 DOI: 10.1016/j.xgen.2025.100778

Sjoerd J D Tjalsma, Niels J Rinzema, Marjon J A M Verstegen, Michelle J Robers, Andrea Nieto-Aliseda, Richard A Gremmen, Amin Allahyar, Mauro J Muraro, Peter H L Krijger, Wouter de Laat

{"title":"Long-range enhancer-controlled genes are hypersensitive to regulatory factor perturbations.","authors":"Sjoerd J D Tjalsma, Niels J Rinzema, Marjon J A M Verstegen, Michelle J Robers, Andrea Nieto-Aliseda, Richard A Gremmen, Amin Allahyar, Mauro J Muraro, Peter H L Krijger, Wouter de Laat","doi":"10.1016/j.xgen.2025.100778","DOIUrl":"10.1016/j.xgen.2025.100778","url":null,"abstract":"Cell-type-specific gene activation is regulated by enhancers, sometimes located at large genomic distances from target gene promoters. Whether distal enhancers require specific factors to orchestrate gene regulation remains unclear. Here, we used enhancer distance-controlled reporter screens to find candidate factors. We depleted them and employed activity-by-contact predictions to genome-wide classify genes based on enhancer distance. Predicted distal enhancers typically control tissue-restricted genes and often are strong enhancers. We find cohesin, but also mediator, most specifically required for long-range activation, with cohesin repressing short-range gene activation and prioritizing distal over proximal HBB genes competing for shared enhancers. Long-range controlled genes are also most sensitive to perturbations of other regulatory proteins and to BET inhibitor JQ1, this being more a consequence of their distinct enhancer features than distance. Our work predicts that lengthening of intervening sequences can help limit the expression of target genes to specialized cells with optimal trans-factor environments.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100778"},"PeriodicalIF":11.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Capturing cell-type-specific activities of cis-regulatory elements from peak-based single-cell ATAC-seq.

IF 11.1

Cell genomics Pub Date : 2025-03-12 Epub Date: 2025-03-05 DOI: 10.1016/j.xgen.2025.100806

Mengjie Chen

引用次数: 0

Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer.

IF 11.1

Cell genomics Pub Date : 2025-03-04 DOI: 10.1016/j.xgen.2025.100807

Jeffrey K Ng, Yilin Chen, Titilope M Akinwe, Hillary B Heins, Elvisa Mehinovic, Yoonhoo Chang, David H Gutmann, Christina A Gurnett, Zachary L Payne, Juana G Manuel, Rachel Karchin, Tychele N Turner

{"title":"Proteome-wide assessment of differential missense variant clustering in neurodevelopmental disorders and cancer.","authors":"Jeffrey K Ng, Yilin Chen, Titilope M Akinwe, Hillary B Heins, Elvisa Mehinovic, Yoonhoo Chang, David H Gutmann, Christina A Gurnett, Zachary L Payne, Juana G Manuel, Rachel Karchin, Tychele N Turner","doi":"10.1016/j.xgen.2025.100807","DOIUrl":"10.1016/j.xgen.2025.100807","url":null,"abstract":"Prior studies examining genomic variants suggest that some proteins contribute to both neurodevelopmental disorders (NDDs) and cancer. While there are several potential etiologies, here, we hypothesize that missense variation in proteins occurs in different clustering patterns, resulting in distinct phenotypic outcomes. This concept was first explored in 1D protein space and expanded using 3D protein structure models. Missense de novo variants were examined from 39,883 families with NDDs and missense somatic variants from 10,543 sequenced tumors covering five The Cancer Genome Atlas (TCGA) cancer types and two Catalog of Somatic Mutations in Cancer (COSMIC) pan-cancer aggregates of tissue types. We find 18 proteins with differential missense variation clustering in NDDs compared to cancers and 19 in cancers relative to NDDs. These proteins may be important for detailed assessments in thinking of future prognostic and therapeutic applications. We establish a framework for interpreting missense patterns in NDDs and cancer, using advances in 3D protein structure prediction.","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100807"},"PeriodicalIF":11.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143617854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genomic garden: From societal and scientific impacts to biodiversity conservation.

IF 11.1

Cell genomics Pub Date : 2025-02-20 DOI: 10.1016/j.xgen.2025.100779

Abner Herbert Lim, Cedric Chuan Young Ng, Jing Han Hong, Ewe Choon Lee, Kenneth Kwek, Patrick Tan, Hazri Kifle, Ivy Ng, Bin Tean Teh

引用次数: 0

Overcoming collaboration barriers in quantitative trait loci analysis.

IF 11.1

Cell genomics Pub Date : 2025-02-12 DOI: 10.1016/j.xgen.2025.100773

Wen Zhang, Xiaohong Wu, Jing Gong