Genome research最新文献

R-loops shape the H2A.Z landscape and promote balanced lineage allocation during differentiation. r环形成H2A。在分化过程中促进平衡的谱系分配。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281088.125

Chun-Hao Chao, Thomas G Fazzio

{"title":"R-loops shape the H2A.Z landscape and promote balanced lineage allocation during differentiation.","authors":"Chun-Hao Chao, Thomas G Fazzio","doi":"10.1101/gr.281088.125","DOIUrl":"https://doi.org/10.1101/gr.281088.125","url":null,"abstract":"R-loops, RNA:DNA hybrids that often form cotranscriptionally, are emerging as key regulators of genome function, yet their roles in shaping chromatin architecture and developmental potential remain incompletely defined. Here, we use inducible Rnaseh1 expression in mouse embryonic stem cells (mESCs) to achieve short-term, global R-loop depletion and to systematically interrogate their impact on chromatin structure and lineage specification. We find that R-loop loss has a minimal effect on steady-state gene expression or self-renewal. Instead, it leads to a striking reduction in H2A.Z occupancy at both active and bivalent promoters, accompanied by increased nucleosome density, revealing a previously unrecognized role for R-loops in maintaining promoter architecture. During gastruloid differentiation, R-loop-depleted mESCs exhibit accelerated ectodermal differentiation, along with dysregulation of lineage-specific transcription factors and impaired cell-cell signaling. Consistent with these alterations, R-loop-depleted cells show widespread perturbations in gene regulatory networks across several early cell types. These findings uncover a critical role for R-loops in shaping the H2A.Z chromatin landscape and preserving balanced lineage trajectories during early development, offering new insights into the epigenomic regulation of stem cell fate.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"36 5","pages":"924-937"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13148237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147837068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Restoring the potency of a neutralizing antibody via guided hypermutation with hyper-antibody editor HAE1. 利用超抗体编辑器引导超突变恢复中和抗体的效力。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281396.125

Yuhong Wang, Yuefeng Guo, Qiuyu Lu, Xinyi Liu, Haoqi Xu, Jiayi Chen, Ruiqi Pi, Shaopeng Yuan, Ziting Yang, Rusen Lu, Fei-Long Meng, Tingting Gan, Jiazhi Hu

{"title":"Restoring the potency of a neutralizing antibody via guided hypermutation with hyper-antibody editor HAE1.","authors":"Yuhong Wang, Yuefeng Guo, Qiuyu Lu, Xinyi Liu, Haoqi Xu, Jiayi Chen, Ruiqi Pi, Shaopeng Yuan, Ziting Yang, Rusen Lu, Fei-Long Meng, Tingting Gan, Jiazhi Hu","doi":"10.1101/gr.281396.125","DOIUrl":"10.1101/gr.281396.125","url":null,"abstract":"Somatic hypermutation (SHM) drives antibody affinity maturation in B cells. By mimicking this process, guided hypermutation (GHM) tools employing CRISPR systems and activation-induced cytidine deaminase (AID) have advanced antibody development. However, GHM-induced mutations in cultured cells exhibit mutation patterns distinct from those observed in natural antibody diversification following in vivo affinity selection. To address this, we engineer a hyper-antibody editor, HAE1, by integrating cytidine and adenine deaminases with a nicked, PAMless Cas9 variant, SpRY, to closely resemble the mutation spectrum of natural SHM. Moreover, to streamline mutation, selection, and validation within the same cells, we develop a dual-expression system in HEK293F cells that allows simultaneous expression of both transmembrane and secreted full-length antibodies. Using this system, we apply HAE1 to the SARS-CoV-2 neutralizing antibody CV07-209 and restore the antibody's binding affinity and neutralization potency against Omicron variants, specifically BA.1, including at least one mutation beyond the reach of current GHM tools. HAE1 thus provides a versatile, high-throughput strategy for expediting antibody evolution, presenting significant potential for therapeutic antibody development and protein engineering.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"1029-1039"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147485470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Using CRISPR barcoding as a molecular clock to capture dynamic processes at single-cell resolution. 利用CRISPR条形码作为分子钟，以单细胞分辨率捕捉动态过程。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.280915.125

Yolanda Andres-Lopez, Alice Santambrogio, Ioannis Kafetzopoulos, Christopher D Todd, Carla El Khouri-Gonzalez, J-Elliot Gonzalez-Alvarez, Celia Alda-Catalinas, Stephen J Clark, Wolf Reik, Irene Hernando-Herraez

{"title":"Using CRISPR barcoding as a molecular clock to capture dynamic processes at single-cell resolution.","authors":"Yolanda Andres-Lopez, Alice Santambrogio, Ioannis Kafetzopoulos, Christopher D Todd, Carla El Khouri-Gonzalez, J-Elliot Gonzalez-Alvarez, Celia Alda-Catalinas, Stephen J Clark, Wolf Reik, Irene Hernando-Herraez","doi":"10.1101/gr.280915.125","DOIUrl":"10.1101/gr.280915.125","url":null,"abstract":"Biological processes are inherently dynamic, yet current methods for capturing temporal changes remain limited. Here, we present scDynaBar, a novel approach that combines CRISPR-Cas9 dynamic barcoding with single-cell sequencing. In this system, genetic barcodes gradually accumulate mutations over time; these barcodes are sequenced alongside the transcriptome of individual cells. We propose that the divergence of these barcodes from the original sequence can serve as a record of the timing of cellular events. To demonstrate the potential of this method, we track the transition from a pluripotent state to a two-cell (2C)-like state in mouse embryonic stem cells (mESCs), providing evidence for the transient nature of the 2C-like state. Additionally, our system shows consistent mutation rates across diverse cell types in a mouse gastruloid model, highlighting its applicability to other biological systems. This approach not only improves our ability to study single-cell dynamics but also opens up new possibilities for recording other temporal signals-in other words, using dynamic barcoding as a molecular clock in individual cells.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"1005-1015"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147814049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Simultaneous modeling of chromatin conformation changes from multiple single-cell interaction maps with ChromMovie. 同时建模染色质构象变化从多个单细胞相互作用图与ChromMovie。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.280985.125

Krzysztof H Banecki, Haoxi Chai, Yijun Ruan, Dariusz Plewczynski

{"title":"Simultaneous modeling of chromatin conformation changes from multiple single-cell interaction maps with ChromMovie.","authors":"Krzysztof H Banecki, Haoxi Chai, Yijun Ruan, Dariusz Plewczynski","doi":"10.1101/gr.280985.125","DOIUrl":"10.1101/gr.280985.125","url":null,"abstract":"The development of 3C-based techniques for analyzing three-dimensional chromatin structure dynamics has driven significant interest in computational methods for 3D chromatin reconstruction. In particular, models based on Hi-C and its single-cell variants, such as scHi-C, have gained widespread popularity. Current approaches for reconstructing the chromatin structure from scHi-C data typically operate by processing one scHi-C map at a time, generating a corresponding 3D chromatin structure as output. Here, we introduce an alternative approach to the whole-genome 3D chromatin structure reconstruction that builds upon existing methods while incorporating the broader context of dynamic cellular processes, such as the cell cycle or cell maturation. Our approach integrates scHi-C contact data with single-cell trajectory information and is based on applying simultaneous modeling of a number of cells ordered along the progression of a given cellular process. The approach is able to successfully recreate known nuclear structures while simultaneously achieving smooth, continuous changes in chromatin structure throughout the cell cycle trajectory. Although both Hi-C-based chromatin reconstruction and cellular trajectory inference are well-developed fields, little effort has been made to bridge the gap between them. To address this, we present ChromMovie, a comprehensive molecular dynamics framework for modeling 3D chromatin structure changes in the context of cellular trajectories. To our knowledge, no existing method effectively leverages both the variability of single-cell Hi-C data and explicit information from estimated cellular trajectories, such as cell cycle progression, to improve chromatin structure reconstruction.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"992-1004"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A genome-wide survey reveals that a diverse array of enhancers coordinates the Drosophila innate immune response. 一项全基因组调查揭示了多种增强子协调果蝇先天免疫反应。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281432.125

Lianne B Cohen, Tamara Hadzic, Caitlin Sauer, Julia R Gibbs, Zeba Wunderlich

{"title":"A genome-wide survey reveals that a diverse array of enhancers coordinates the Drosophila innate immune response.","authors":"Lianne B Cohen, Tamara Hadzic, Caitlin Sauer, Julia R Gibbs, Zeba Wunderlich","doi":"10.1101/gr.281432.125","DOIUrl":"10.1101/gr.281432.125","url":null,"abstract":"To defend against microbes, animals regulate a complex immune response. The Drosophila innate immune system deploys a large transcriptional induction of signaling proteins, antimicrobial effectors, and other critical immune factors. This transcriptional response is encoded in enhancers, cis-regulatory sequences that modulate gene expression by binding transcription factors (TFs). Although enhancers and transcription factor binding sites (TFBSs) have been identified for several immune responsive genes in Drosophila, most enhancers that regulate immune-induced genes are unknown. By identifying enhancers, we can understand how their composition controls expression and contributes to infection outcome. We employ self-transcribing active regulatory-region sequencing (STARR-seq) in a hemocyte-like cell line to identify immune-specific enhancers across the D. melanogaster genome and perform ATAC-seq in hemocytes extracted from adult flies to assess the chromatin state of these enhancers before and after immune stimulus. We identify hundreds of enhancers responsive to IMD stimulation, one of the two primary immune signaling pathways in Drosophila As expected, immune enhancers are enriched for motifs of Relish, an NF-kB factor, and Kay/Jra, a bZip heterodimer pair, involved in the Imd and JNK pathways respectively, compared with enhancers active in unstimulated cells. However, when grouping enhancers by their target gene's expression timing or functional role or by the enhancers' chromatin accessibility pre- or post-stimulus, different groups of TFBS motifs are enriched, suggesting distinct regulatory logic for different parts of the immune response. Identification and characterization of the diverse array of enhancers that regulate the innate immune response expand our understanding of how animals fight infections.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"964-975"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147689740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamic body size evolution during speciation of predatory cichlid fishes in the Lake Malawi superradiation. 马拉维湖超辐射中捕食性慈鲷物种形成过程中动态体型演化。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281193.125

Liandong Yang, Holly Scott, Benjamin P Ngatunga, Asilatu H Shechonge, George F Turner, Martin J Genner

{"title":"Dynamic body size evolution during speciation of predatory cichlid fishes in the Lake Malawi superradiation.","authors":"Liandong Yang, Holly Scott, Benjamin P Ngatunga, Asilatu H Shechonge, George F Turner, Martin J Genner","doi":"10.1101/gr.281193.125","DOIUrl":"https://doi.org/10.1101/gr.281193.125","url":null,"abstract":"Evolutionary divergence in body size is common in animal adaptive radiations and is often associated with differences in key ecological traits, including habitat use and prey consumption. Here we characterize a notable case of body size-associated adaptive radiation in a group of predatory open water cichlid fish species from the Lake Malawi catchment. Using whole-genome sequences, we show that body size differences have evolved multiple times in the focal genus, Rhamphochromis, and that the group possesses well-defined signals of ancient interspecific hybridization. We identify genetic variants strongly associated with body size and show that these variants are connected to genes enriched for functions in vertebrate skeletal and nervous system development. We focus our analyses on two species of Rhamphochromis endemic to Lake Kingiri, a small (600 m diameter) crater lake geographically isolated from the main body of Lake Malawi but within the catchment. We show that these two ecomorphologically divergent sympatric species-one small-bodied, the other larger-bodied-share a unique common ancestor and diverged from one another ∼2000 years ago. We demonstrate strong directional selection focused on the larger-bodied Kingiri species, specifically on genetic variants connected to genes with anatomical development and nervous system function. Collectively, these results are supportive of body size-associated speciation taking place rapidly in the Lake Malawi cichlid fish superradiation. We conclude that body size-associated genetic variants have been important targets of selection during large-scale cichlid fish diversification, including in a crater lake sympatric speciation context.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"36 5","pages":"949-963"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147836978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hash functions in nucleotide sequence analysis. 核苷酸序列分析中的哈希函数。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281453.125

Ke Chen, Xiang Li, Qian Shi, Mingfu Shao, Paul Medvedev

引用次数: 0

Incorporating valuable prior knowledge to improve deep learning prediction of genetic perturbation responses. 结合有价值的先验知识，提高遗传扰动响应的深度学习预测。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281523.125

Xiuhao Fu, Chao Yang, Chunyan Cui, Aoyun Geng, Yidi Sun, Chao Zha, Feifei Cui, Leyi Wei, Quan Zou, Xin Gao, Zilong Zhang

{"title":"Incorporating valuable prior knowledge to improve deep learning prediction of genetic perturbation responses.","authors":"Xiuhao Fu, Chao Yang, Chunyan Cui, Aoyun Geng, Yidi Sun, Chao Zha, Feifei Cui, Leyi Wei, Quan Zou, Xin Gao, Zilong Zhang","doi":"10.1101/gr.281523.125","DOIUrl":"10.1101/gr.281523.125","url":null,"abstract":"Genetic perturbation response prediction plays a critical role in virtual cell research, yet the performance of current deep learning models still leaves room for improvement. In this study, we present a prior-guided response inference model (PRIM) that leverages a valuable priori knowledge of gene expression in control cells to model the effects of perturbations at the cellular level. This allows PRIM to predict the amount of change in gene expression after perturbation to better approximate the real situation. Compared with existing deep learning approaches, PRIM achieves superior performance across multiple data sets and notable advantages in predicting combinatorial perturbation responses. Moreover, it is more lightweight than current deep learning models and enables faster forward inference. Importantly, PRIM effectively captures nonadditive genetic interactions and shows the potential to uncover associations between combinatorial perturbations and new biologically meaningful phenotypes. These findings provide new insights into the application of deep learning for predicting cellular responses to genetic perturbations.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"1040-1052"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dynamics and consequences of differential RNA isoform production during cardiomyocyte fate determination and early-stage maturation. 在心肌细胞命运决定和早期成熟过程中差异RNA异构体产生的动力学和后果。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281150.125

Joanna Delimata-Raczek, Natalia Koralewska, Bart Krist, Magdalena Rakoczy, Marek Figlerowicz, Ireneusz Stolarek

{"title":"Dynamics and consequences of differential RNA isoform production during cardiomyocyte fate determination and early-stage maturation.","authors":"Joanna Delimata-Raczek, Natalia Koralewska, Bart Krist, Magdalena Rakoczy, Marek Figlerowicz, Ireneusz Stolarek","doi":"10.1101/gr.281150.125","DOIUrl":"10.1101/gr.281150.125","url":null,"abstract":"Cellular identity is dictated by precise transcriptomic programs; however, the mechanisms that dynamically shape the transcriptome by producing diverse RNA isoforms remain incompletely understood. Here, through longitudinal transcriptomic profiling of cardiomyogenesis, we delineate pervasive RNA isoform switching across the developmental trajectory of cardiac differentiation. We show that the changes in isoform accumulation are largely decoupled from shifts in overall gene expression levels and arise predominantly from alternative transcription start and termination rather than splicing. This regulatory layer preferentially targets genes essential for cardiac function, specifically those encoding contractile machinery and ion channel complexes. We demonstrate that genes undergoing isoform switching without changing overall expression constitute a functionally distinct cohort, establishing isoform switching as an independent layer of gene regulation. Furthermore, we characterize stage-specific expression dynamics for numerous RNA-binding proteins and link their expression to specific isoform switching events. Our findings support a coordinated mechanism for the targeted regulation of RNA diversity, positioning isoform switching as a primary driver of transcriptomic maturation during lineage commitment.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"903-915"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147615954","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lignature provides a curated resource of ligand-induced transcriptomic signatures for signaling inference. 木质素为信号推断提供了配体诱导的转录组特征的策划资源。

IF 5.5 2区生物学

Genome research Pub Date : 2026-05-06 DOI: 10.1101/gr.281287.125

Ying Xin, Md Amanullah, Cheng Qian, Chingmo Zhou, Jiang Qian

{"title":"Lignature provides a curated resource of ligand-induced transcriptomic signatures for signaling inference.","authors":"Ying Xin, Md Amanullah, Cheng Qian, Chingmo Zhou, Jiang Qian","doi":"10.1101/gr.281287.125","DOIUrl":"10.1101/gr.281287.125","url":null,"abstract":"Ligand-receptor interactions mediate intercellular communication, inducing transcriptional changes that regulate physiological and pathological processes. Ligand-induced transcriptomic signatures can be used to infer ligand activity; however, the absence of a comprehensive set of ligand-response signatures has limited their practical application in predicting ligand-receptor interactions. To bridge this gap, we develop Lignature, a curated database encompassing intracellular transcriptomic signatures for 362 human ligands, significantly expanding the repertoire of ligands with available intracellular response signatures such as CytoSig and ImmuneDictionary. Lignature compiles signatures from published transcriptomic data sets, generating both gene- and pathway-based signatures for each ligand. We apply Lignature to prioritize ligand-associated transcriptional activity in controlled in vitro experiments and real-world single-cell sequencing data sets. Across these settings, Lignature consistently improves the prioritization of experimentally supported ligands compared with existing approaches. We additionally develop a regression-based framework to model combinatorial regulation by multiple ligands. These results establish Lignature as a robust platform for ligand signaling inference, providing a powerful tool to explore ligand-receptor interactions across diverse experimental and physiological contexts.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"1067-1079"},"PeriodicalIF":5.5,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0