Single-nucleus transcriptomic mapping uncovers targets for traumatic brain injury [RESOURCES]
In this study, we meticulously mapped the transcriptome atlas of murine SVZ and its responses to mTBI at the single-cell level. We observed cell-specific gene expression changes following mTBI and unveiled diverse cell-to-cell interaction networks that influence a wide array of cellular processes. Moreover, we reported novel neurogenesis lineage trajectories and related key transcription factors, which we subsequently validated through loss-of-function experiments. Specifically, we validated the role of Tcf7l1, a cell cycle gene regulator, in promoting neural stem cell differentiation towards the neuronal lineage after mTB...
Source: Genome Research - September 20, 2023 Category: Genetics & Stem Cells Authors: Yang, Q., Zhang, L., Li, M., Xu, Y., Chen, X., Yuan, R., Ou, X., He, M., Liao, M., Zhang, L., Dai, H., Lv, M., Xie, X., Liang, W., Chen, X. Tags: RESOURCES Source Type: research
Spatial transcriptomics reveals asymmetric cellular responses to injury in the regenerating spiny mouse (Acomys) ear [RESOURCES]
In contrast to other mammals, the spiny mouse (Acomys) regenerates skin and ear tissue, which includes hair follicles, glands, and cartilage, in a scar-free manner. Ear punch regeneration is asymmetric with only the proximal wound side participating in regeneration. Here, we show that cues originating from the proximal side are required for normal regeneration and use spatially resolved transcriptomics (tomo-seq) to understand the molecular and cellular events underlying this process. Analyzing gene expression across the ear and comparing expression modules between proximal and distal wound sides, we identify asymmetric ge...
Source: Genome Research - September 19, 2023 Category: Genetics & Stem Cells Authors: van Beijnum, H., Koopmans, T., Tomasso, A., Disela, V., te Lindert, S., Bakkers, J., Alemany, A., Berezikov, E., Bartscherer, K. Tags: RESOURCES Source Type: research
Historical RNA expression profiles from the extinct Tasmanian tiger [RESEARCH]
Paleogenomics continues to yield valuable insights into the evolution, population dynamics, and ecology of our ancestors and other extinct species. However, DNA sequencing cannot reveal tissue-specific gene expression, cellular identity, or gene regulation, which are only attainable at the transcriptional level. Pioneering studies have shown that useful RNA can be extracted from ancient specimens preserved in permafrost and historical skins from extant canids, but no attempts have been made so far on extinct species. We extract, sequence, and analyze historical RNA from muscle and skin tissue of a ~130-year-old Tasmanian t...
Source: Genome Research - September 19, 2023 Category: Genetics & Stem Cells Authors: Marmol-Sanchez, E., Fromm, B., Oskolkov, N., Pochon, Z., Kalogeropoulos, P., Eriksson, E., Biryukova, I., Sekar, V., Ersmark, E., Andersson, B., Dalen, L., Friedländer, M. R. Tags: RESEARCH Source Type: research
Unraveling the palindromic and nonpalindromic motifs of retroviral integration site sequences by statistical mixture models [METHOD]
A weak palindromic nucleotide motif is the hallmark of retroviral integration site alignments. Given that the majority of target sequences are not palindromic, the current model explains the symmetry by an overlap of the nonpalindromic motif present on one of the half-sites of the sequences. Here, we show that the implementation of multicomponent mixture models allows for different interpretations consistent with the existence of both palindromic and nonpalindromic submotifs in the sets of integration site sequences. We further show that the weak palindromic motifs result from freely combined site-specific submotifs restri...
Source: Genome Research - September 19, 2023 Category: Genetics & Stem Cells Authors: Miklik, D., Grim, J., Elleder, D., Hejnar, J. Tags: METHOD Source Type: research
A Chinese indicine pangenome reveals a wealth of novel structural variants introgressed from other Bos species [RESEARCH]
Chinese indicine cattle harbor a much higher genetic diversity compared with other domestic cattle, but their genome architecture remains uninvestigated. Using PacBio HiFi sequencing data from 10 Chinese indicine cattle across southern China, we assembled 20 high-quality partially phased genomes and integrated them into a multiassembly graph containing 148.5 Mb (5.6%) of novel sequence. We identified 156,009 high-confidence nonredundant structural variants (SVs) and 206 SV hotspots spanning ~195 Mb of gene-rich sequence. We detected 34,249 archaic introgressed fragments in Chinese indicine cattle covering 1.93 Gb (73.3%) o...
Source: Genome Research - September 15, 2023 Category: Genetics & Stem Cells Authors: Dai, X., Bian, P., Hu, D., Luo, F., Huang, Y., Jiao, S., Wang, X., Gong, M., Li, R., Cai, Y., Wen, J., Yang, Q., Deng, W., Nanaei, H. A., Wang, Y., Wang, F., Zhang, Z., Rosen, B. D., Heller, R., Jiang, Y. Tags: RESEARCH Source Type: research
Ultra-long-range interactions between active regulatory elements [RESEARCH]
Contacts between enhancers and promoters are thought to relate to their ability to activate transcription. Investigating factors that contribute to such chromatin interactions is therefore important for understanding gene regulation. Here, we have determined contact frequencies between millions of pairs of cis-regulatory elements from chromosome conformation capture data sets and analyzed a collection of hundreds of DNA-binding factors for binding at regions of enriched contacts. This analysis revealed enriched contacts at sites bound by many factors associated with active transcription. We show that active regulatory elem...
Source: Genome Research - September 15, 2023 Category: Genetics & Stem Cells Authors: Friman, E. T., Flyamer, I. M., Marenduzzo, D., Boyle, S., Bickmore, W. A. Tags: RESEARCH Source Type: research
Allele-specific RNA N6-methyladenosine modifications reveal functional genetic variants in human tissues [METHOD]
An intricate network of cis- and trans-elements acts on RNA N6-methyladenosine (m6A), which in turn may affect gene expression and, ultimately, human health. A complete understanding of this network requires new approaches to accurately measure the subtle m6A differences arising from genetic variants, many of which have been associated with common diseases. To address this gap, we developed a method to accurately and sensitively detect transcriptome-wide allele-specific m6A (ASm6A) from MeRIP-seq data and applied it to uncover 12,056 high-confidence ASm6A modifications from 25 human tissues. We also identified 1184 putativ...
Source: Genome Research - September 15, 2023 Category: Genetics & Stem Cells Authors: Cao, S., Zhu, H., Cui, J., Liu, S., Li, Y., Shi, J., Mo, J., Wang, Z., Wang, H., Hu, J., Chen, L., Li, Y., Xia, L., Xiao, S. Tags: METHOD Source Type: research
Diffusion-enhanced characterization of 3D chromatin structure reveals its linkage to the interactome [METHOD]
The interactome networks at the DNA, RNA, and protein levels are crucial for cellular functions, and the diverse variations of these networks are heavily involved in the establishment of different cell states. We have developed a diffusion-based method, Hi-C to geometry (CTG), to obtain reliable geometric information on the chromatin from Hi-C data. CTG produces a consistent and reproducible framework for the 3D genomic structure and provides a reliable and quantitative understanding of the alterations of genomic structures under different cellular conditions. The genomic structure yielded by CTG serves as an architectural...
Source: Genome Research - September 15, 2023 Category: Genetics & Stem Cells Authors: He, Y., Xue, Y., Wang, J., Huang, Y., Liu, L., Huang, Y., Gao, Y. Q. Tags: METHOD Source Type: research
Transposable elements drive the evolution of metazoan zinc finger genes [RESEARCH]
Cys2-His2 zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. ZNF evolution is highly dynamic and characterized by the rapid expansion and contraction of numerous subfamilies across the animal phylogeny. The forces and mechanisms underlying rapid ZNF evolution remain poorly understood, but there is growing evidence that, in tetrapods, the targeting and repression of lineage-specific transposable elements (TEs) plays a critical role in the evolution of the Krüppel-associated box ZNF (KZNF) subfamily. Currently, it is unknown whether this function and coevolutionary relationship is...
Source: Genome Research - September 15, 2023 Category: Genetics & Stem Cells Authors: Wells, J. N., Chang, N.-C., McCormick, J., Coleman, C., Ramos, N., Jin, B., Feschotte, C. Tags: RESEARCH Source Type: research
Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins [RESEARCH]
A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein, we identify the molecular mechanisms involved, showing that ...
Source: Genome Research - September 14, 2023 Category: Genetics & Stem Cells Authors: Avolio, R., Agliarulo, I., Criscuolo, D., Sarnataro, D., Auriemma, M., De Lella, S., Pennacchio, S., Calice, G., Ng, M. Y., Giorgi, C., Pinton, P., Cooperman, B. S., Landriscina, M., Esposito, F., Matassa, D. S. Tags: RESEARCH Source Type: research
Nucleosome repositioning in chronic lymphocytic leukaemia [RESEARCH]
The location of nucleosomes in the human genome determines the primary chromatin structure and regulates access to regulatory regions. However, genome-wide information on deregulated nucleosome occupancy and its implications in primary cancer cells is scarce. Here, we conducted a genome-wide comparison of high-resolution nucleosome maps in peripheral-blood B cells from patients with chronic lymphocytic leukaemia (CLL) and healthy individuals at single base pair resolution. Our investigation uncovered significant changes of nucleosome positioning in CLL. Globally, the spacing between nucleosomes – the nucleosome repea...
Source: Genome Research - September 12, 2023 Category: Genetics & Stem Cells Authors: Piroeva, K. V., McDonald, C., Xanthopoulos, C., Fox, C., Clarkson, C. T., Mallm, J.-P., Vainshtein, Y., Ruje, L., Klett, L. C., Stilgenbauer, S., Mertens, D., Kostareli, E., Rippe, K., Teif, V. B. Tags: RESEARCH Source Type: research
Chromatin loop dynamics during cellular differentiation are associated with changes to both anchor and internal regulatory features [RESEARCH]
Three-dimensional (3D) chromatin structure has been shown to play a role in regulating gene transcription during biological transitions. Although our understanding of loop formation and maintenance is rapidly improving, much less is known about the mechanisms driving changes in looping and the impact of differential looping on gene transcription. One limitation has been a lack of well-powered differential looping data sets. To address this, we conducted a deeply sequenced Hi-C time course of megakaryocyte development comprising four biological replicates and 6 billion reads per time point. Statistical analysis revealed 150...
Source: Genome Research - September 12, 2023 Category: Genetics & Stem Cells Authors: Bond, M. L., Davis, E. S., Quiroga, I. Y., Dey, A., Kiran, M., Love, M. I., Won, H., Phanstiel, D. H. Tags: RESEARCH Source Type: research
Loss of epigenetic suppression of retrotransposons with oncogenic potential in aging mammary luminal epithelial cells [RESEARCH]
We report here that several TE subfamilies function as regulatory elements in normal LEps, and a subset of these display consistent methylation changes with age. Methylation changes at these TEs occurred at lineage-specific transcription factor binding sites, consistent with loss of lineage specificity. Whereas TEs mainly showed methylation loss, CpG islands (CGIs) that are targets of the Polycomb repressive complex 2 (PRC2) show a gain of methylation in aging cells. Many TEs with methylation loss in aging LEps have evidence of regulatory activity in breast cancer samples. We furthermore show that methylation changes at TE...
Source: Genome Research - September 11, 2023 Category: Genetics & Stem Cells Authors: Senapati, P., Miyano, M., Sayaman, R. W., Basam, M., Leung, A., LaBarge, M. A., Schones, D. E. Tags: RESEARCH Source Type: research
Extensive variation in germline de novo mutations in Poecilia reticulata [RESEARCH]
The rate of germline mutation is fundamental to evolutionary processes, as it generates the variation upon which selection acts. The guppy, Poecilia reticulata, is a model of rapid adaptation, however the relative contribution of standing genetic variation versus de novo mutation (DNM) to evolution in this species remains unclear. Here, we use pedigree-based approaches to quantify and characterize germline DNMs in three large guppy families. Our results suggest germline mutation rate in the guppy varies substantially across individuals and families. Most DNMs are shared across multiple siblings, suggesting they arose durin...
Source: Genome Research - September 6, 2023 Category: Genetics & Stem Cells Authors: Lin, Y., Darolti, I., van der Bijl, W., Morris, J., Mank, J. E. Tags: RESEARCH Source Type: research
Copy number variation alters local and global mutational tolerance [RESEARCH]
Copy number variants (CNVs), duplications and deletions of genomic sequences, contribute to evolutionary adaptation but can also confer deleterious effects and cause disease. Whereas the effects of amplifying individual genes or whole chromosomes (i.e., aneuploidy) have been studied extensively, much less is known about the genetic and functional effects of CNVs of differing sizes and structures. Here, we investigated Saccharomyces cerevisiae (yeast) strains that acquired adaptive CNVs of variable structures and copy numbers following experimental evolution in glutamine-limited chemostats. Although beneficial in the select...
Source: Genome Research - August 31, 2023 Category: Genetics & Stem Cells Authors: Avecilla, G., Spealman, P., Matthews, J., Caudal, E., Schacherer, J., Gresham, D. Tags: RESEARCH Source Type: research
