Lujia Chen, Xiangduo Kong, Kevin G Johnston, Ali Mortazavi, Todd C Holmes, Zhiqun Tan, Kyoko Yokomori, Xiangmin Xu
Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal de-repression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use MERFISH (Multiplexed Error Robust Fluorescent In Situ Hybridization) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution...
May 22, 2024: Genome Research
Milad Razavi-Mohseni, Weitai Huang, Yu Amanda Guo, Dustin Shigaki, Shamaine Ho, Patrick Tan, Anders Skanderup, Michael A Beer
Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). While gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood. Here we use ATAC-seq and RNA-seq from a compendium of gastric cancer cell lines and primary tumors to detect drivers of regulatory state changes and their transcriptional responses...
May 22, 2024: Genome Research
Zan Koenig, Mary T Yohannes, Lethukuthula L Nkambule, Xuefang Zhao, Julia K Goodrich, Heesu Ally Kim, Michael W Wilson, Grace Tiao, Stephanie P Hao, Nareh Sahakian, Katherine R Chao, Mark A Walker, Yunfei Lyu, Heidi Rehm, Benjamin M Neale, Michael E Talkowski, Mark J Daly, Harrison Brand, Konrad J Karczewski, Elizabeth G Atkinson, Alicia R Martin
Underrepresented populations are often excluded from genomic studies due in part to a lack of resources supporting their analyses. The 1000 Genomes Project (1kGP) and Human Genome Diversity Project (HGDP), which have recently been sequenced to high coverage, are valuable genomic resources because of the global diversity they capture and their open data sharing policies. Here, we harmonized a high quality set of 4,094 whole genomes from 80 populations in the HGDP and 1kGP with data from the Genome Aggregation Database (gnomAD) and identified over 153 million high-quality SNVs, indels, and SVs...
May 15, 2024: Genome Research
Satyam Srivastav, Cedric Feschotte, Andrew Clark
The piRNA pathway is conserved to repress transposable element (TE) activity in the animal germline via a specialized class of small RNAs called piwi-interacting RNAs (piRNAs). piRNAs are produced from discrete genomic regions called piRNA clusters (piCs). While the molecular processes by which piCs function are relatively well understood in Drosophila melanogaster , much less is known about the origin and evolution of piCs in this or any other species. To investigate piC origin and evolution, we use a population genomics approach to compare piC activity and sequence composition across 8 geographically distant strains of D...
May 15, 2024: Genome Research
Yalan Sheng, Yuanyuan Wang, Wentao Yang, Xue Qing Wang, Jiuwei Lu, Bo Pan, Bei Nan, Yongqiang Liu, Fei Ye, Chun Li, Jikui Song, Yali Dou, Shan Gao, Yifan Liu
While DNA N6-adenine methylation (6mA) is best known in prokaryotes, its presence in eukaryotes has generated great interest recently. Biochemical and genetic evidence supports that AMT1, a MT-A70 family methyltransferase (MTase), is crucial for 6mA deposition in unicellular eukaryotes. Nonetheless, 6mA transmission mechanism remains to be elucidated. Taking advantage of Single Molecule Real-Time Circular Consensus Sequencing (SMRT CCS), here we provide definitive evidence for semiconservative transmission of 6mA in Tetrahymena thermophila In wild-type (WT) cells, 6mA occurs at the self-complementary ApT dinucleotide, mostly in full methylation (full-6mApT); after DNA replication, hemi-methylation (hemi-6mApT) is transiently present on the parental strand, opposite to the daughter strand readily labeled by 5-bromo-2'-deoxyuridine (BrdU)...
May 14, 2024: Genome Research
Qingpo Cai, Yinghao Fu, Cheng Lyu, Zihe Wang, Shun Rao, Jessica A Alvarez, Yun Bai, Jian Kang, Tianwei Yu
Omics methods are widely used in basic biology and translational medicine research. More and more omics data are collected to explain the impact of certain risk factors on clinical outcomes. To explain the mechanism of the risk factors, a core question is how to find the genes/proteins/metabolites that mediate their effects on the clinical outcome. Mediation analysis is a modeling framework to study the relationship between risk factors and pathological outcomes, via mediator variables. However, high-dimensional omics data are far more challenging than traditional data: (1) From tens of thousands of genes, can we overcome the curse of dimensionality to reliably select a set of mediators? (2) How do we ensure that the selected mediators are functionally consistent? (3) Many biological mechanisms contain nonlinear effects...
May 7, 2024: Genome Research
Jack A S Tierney, Michał Świrski, Håkon Tjeldnes, Jonathan M Mudge, Joanna Kufel, Nicola Whiffin, Eivind Valen, Pavel V Baranov
The application of ribosome profiling has revealed an unexpected abundance of translation in addition to that responsible for the synthesis of previously annotated protein-coding regions. Multiple short sequences have been found to be translated within single RNA molecules, within both annotated protein-coding and noncoding regions. The biological significance of this translation is a matter of intensive investigation. However, current schematic or annotation-based representations of mRNA translation generally do not account for the apparent multitude of translated regions within the same molecules...
May 7, 2024: Genome Research
Christine R Keenan, Hannah D Coughlan, Nadia Iannarella, Andres Tapia Del Fierro, Andrew Keniry, Timothy M Johanson, Wing Fuk Chan, Alexandra L Garnham, Lachlan W Whitehead, Marnie E Blewitt, Gordon K Smyth, Rhys S Allan
H3K9me3-dependent heterochromatin is critical for the silencing of repeat-rich pericentromeric regions and also has key roles in repressing lineage-inappropriate protein-coding genes in differentiation and development. Here, we investigate the molecular consequences of heterochromatin loss in cells deficient in both SUV39H1 and SUV39H2 (Suv39DKO), the major mammalian histone methyltransferase enzymes that catalyze heterochromatic H3K9me3 deposition. We reveal a paradoxical repression of protein-coding genes in Suv39DKO cells, with these differentially expressed genes principally in euchromatic (Tn5-accessible, H3K4me3- and H3K27ac-marked) rather than heterochromatic (H3K9me3-marked) or polycomb (H3K27me3-marked) regions...
May 6, 2024: Genome Research
Dhanur P Iyer, Lambert Moyon, Lars Wittler, Chieh-Yu Cheng, Francisca R Ringeling, Stefan Canzar, Annalisa Marsico, Aydan Bulut-Karslioğlu
Dormancy is a key feature of stem cell function in adult tissues as well as in embryonic cells in the context of diapause. The establishment of dormancy is an active process that involves extensive transcriptional, epigenetic, and metabolic rewiring. How these processes are coordinated to successfully transition cells to the resting dormant state remains unclear. Here we show that microRNA activity, which is otherwise dispensable for preimplantation development, is essential for the adaptation of early mouse embryos to the dormant state of diapause...
May 6, 2024: Genome Research
Stacey E P Joosten, Sebastian Gregoricchio, Suzan Stelloo, Elif Yapıcı, Chia-Chi Flora Huang, Kerim Yavuz, Maria Donaldson Collier, Tunç Morova, Umut Berkay Altintaş, Yongsoo Kim, Sander Canisius, Cathy B Moelans, Paul J van Diest, Gozde Korkmaz, Nathan A Lack, Michiel Vermeulen, Sabine C Linn, Wilbert Zwart
Estrogen Receptor 1 (ESR1; also known as ERα, encoded by ESR1 gene) is the main driver and prime drug target in luminal breast cancer. ESR1 chromatin binding is extensively studied in cell lines and a limited number of human tumors, using consensi of peaks shared among samples. However, little is known about inter-tumor heterogeneity of ESR1 chromatin action, along with its biological implications. Here, we use a large set of ESR1 ChIP-seq data from 70 ESR1+ breast cancers to explore inter-patient heterogeneity in ESR1 DNA binding to reveal a striking inter-tumor heterogeneity of ESR1 action...
May 6, 2024: Genome Research
Elaine Huang, Clara Frydman, Xinshu Xiao
RNA modifications, also termed epitranscriptomic marks, encompass chemical alterations to individual nucleotides, including processes such as methylation and editing. These marks contribute to a wide range of biological processes, many of which are related to host immune system defense. The functions of immune-related RNA modifications can be categorized into three main groups: regulation of immunogenic RNAs, control of genes involved in innate immune response, and facilitation of adaptive immunity. Here, we provide an overview of recent research findings that elucidate the contributions of RNA modifications to each of these processes...
May 3, 2024: Genome Research
Leandros Boukas, Teresa Romeo Luperchio, Afrooz Razi, Kasper D Hansen, Hans T Bjornsson
Many Mendelian developmental disorders caused by coding variants in epigenetic regulators have now been discovered. Epigenetic regulators are broadly expressed, and each of these disorders typically exhibits phenotypic manifestations from many different organ systems. An open question is whether the chromatin disruption - the root of the pathogenesis - is similar in the different disease-relevant cell types. This is possible in principle, since all these cell types are subject to effects from the same causative gene, that has the same kind of function (e...
May 3, 2024: Genome Research
Hasindu Gamaarachchi, James Ferguson, Hiruna Samarakoon, Kisaru Liyanage, Sri Parameswaran, Ira Deveson
In silico simulation of high-throughput sequencing data is a technique used widely in the genomics field. However, there is currently a lack of effective tools for creating simulated data from nanopore sequencing devices, which measure DNA or RNA molecules in the form of time-series current signal data. Here, we introduce Squigulator, a fast and simple tool for simulation of realistic nanopore signal data. Squigulator takes a reference genome, transcriptome or read sequences and generates corresponding raw nanopore signal data...
May 1, 2024: Genome Research
Brian S Roberts, Ashlyn G Anderson, Chris Partridge, Gregory M Cooper, Richard M Myers
Differential gene expression in response to perturbations is mediated at least in part by changes in binding of transcription factors (TFs) and other proteins at specific genomic regions. Association of these cis -regulatory elements (CREs) with their target genes is a challenging task that is essential to address many biological and mechanistic questions. Many current approaches rely on chromatin conformation capture techniques or single-cell correlational methods to establish CRE-to-gene associations. These methods can be effective but have limitations, including resolution, gaps in detectable association distances, and cost...
April 17, 2024: Genome Research
Karan K Smith, Jesse D Moreira, Callum R Wilson, June O Padera, Ashlee N Lamason, Liying Xue, Deepa M Gopal, David B Flynn, Jessica L Fetterman
Mitochondrial DNA (mtDNA) variants cause a range of diseases from severe pediatric syndromes to aging-related conditions. The percentage of mtDNA copies carrying a pathogenic variant, variant allele frequency (VAF), must reach a threshold before a biochemical defect occurs, termed the biochemical threshold. Whether the often-cited biochemical threshold of >60% VAF is similar across mtDNA variants and cell types is unclear. In our systematic review, we sought to identify the biochemical threshold of mtDNA variants in relation to VAF by human tissue/cell type...
April 16, 2024: Genome Research
Ryan Lorig-Roach, Melissa Meredith, Jean Monlong, Miten Jain, Hugh Olsen, Brandy McNulty, David Porubsky, Tessa Montague, Julian Lucas, Chris Condon, Jordan M Eizenga, Sissel Juul, Sean McKenzie, Sara E Simmonds, Jimin Park, Mobin Asri, Sergey Koren, Evan Eichler, Richard Axel, Bruce Martin, Paolo Carnevali, Karen Miga, Benedict Paten
Reference-free genome phasing is vital for understanding allele inheritance and the impact of single-molecule DNA variation on phenotypes. To achieve thorough phasing across homozygous or repetitive regions of the genome, long-read sequencing technologies are often used to perform phased de novo assembly. As a step toward reducing the cost and complexity of this type of analysis, we describe new methods for accurately phasing Oxford Nanopore Technologies (ONT) sequence data with the Shasta genome assembler and a modular tool for extending phasing to the chromosome scale called GFAse...
April 16, 2024: Genome Research
Charles Plessy, Michael J Mansfield, Aleksandra Bliznina, Aki Masunaga, Charlotte West, Yongkai Tan, Andrew W Liu, Jan Grašič, María Sara Del Río Pisula, Gaspar Sánchez-Serna, Marc Fabrega-Torrus, Alfonso Ferrández-Roldán, Vittoria Roncalli, Pavla Navratilova, Eric M Thompson, Takeshi Onuma, Hiroki Nishida, Cristian Cañestro, Nicholas M Luscombe
Genome structural variations within species are rare. How selective constraints preserve gene order and chromosome structure is a central question in evolutionary biology that remains unsolved. Our sequencing of several genomes of the appendicularian tunicate Oikopleura dioica around the globe reveals extreme genome scrambling caused by thousands of chromosomal rearrangements, although showing no obvious morphological differences between these animals. The breakpoint accumulation rate is an order of magnitude higher than in ascidian tunicates, nematodes, Drosophila, or mammals...
April 15, 2024: Genome Research
Yinchun Zhong, Yan Yang, Xiaolin Wang, Bingbing Ren, Xueren Wang, Ge Shan, Liang Chen
Exon-intron circRNAs (EIciRNAs) are a circRNA subclass with retained introns. Global features of EIciRNAs remain largely unexplored, mainly owing to the lack of bioinformatic tools. The regulation of intron retention (IR) in EIciRNAs and the associated functionality also require further investigation. We developed a framework, FEICP, which efficiently detected EIciRNAs from high-throughput sequencing (HTS) data. EIciRNAs are distinct from exonic circRNAs (EcircRNAs) in aspects such as with larger length, localization in the nucleus, high tissue specificity, and enrichment mostly in the brain...
April 12, 2024: Genome Research
João L Reis-Cunha, Samuel A Pimenta-Carvalho, Laila V Almeida, Anderson Coqueiro-Dos-Santos, Catarina A Marques, Jennifer A Black, Jeziel Damasceno, Richard McCulloch, Daniella C Bartholomeu, Daniel C Jeffares
Aneuploidy is widely observed in both unicellular and multicellular eukaryotes, usually associated with adaptation to stress conditions. Chromosomal duplication stability is a tradeoff between the fitness cost of having unbalanced gene copies and the potential fitness gained from increased dosage of specific advantageous genes. Trypanosomatids, a family of protozoans that include species that cause neglected tropical diseases, are a relevant group to study aneuploidies. Their life cycle has several stressors that could select for different patterns of chromosomal duplications and/or losses, and their nearly universal use of polycistronic transcription increases their reliance on gene expansion/contraction, as well as post-transcriptional control as mechanisms for gene expression regulation...
April 11, 2024: Genome Research
Hassan Bukhari, Vanitha Nithianadam, Rachel A Battaglia, Anthony Cicalo, Souvarish Sarkar, Aram Comjean, Yanhui Hu, Matthew J Leventhal, Xianjun Dong, Mel B Feany
Missense mutations in the gene encoding the microtubule-associated protein tau cause autosomal dominant forms of frontotemporal dementia. Multiple models of frontotemporal dementia based on transgenic expression of human tau in experimental model organisms, including Drosophila , have been described. These models replicate key features of the human disease, but do not faithfully recreate the genetic context of the human disorder. Here we use CRISPR-Cas mediated gene editing to model frontotemporal dementia caused by the tau P301L mutation by creating the orthologous mutation, P251L, in the endogenous Drosophila tau gene...
April 10, 2024: Genome Research
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