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{"title":"Diet-induced obesity mediated through Estrogen-Related Receptor α is independent of intestinal function","authors":"Kiranmayi Vemuri, Jahangir Iqbal, S. Kumar, Alexandra Logerfo, Michael P. Verzi","doi":"10.1101/2024.07.10.602978","DOIUrl":"https://doi.org/10.1101/2024.07.10.602978","url":null,"abstract":"Obesity has become an epidemic, prompting advances in therapies targeting this condition. Estrogen-related receptor α (ESRRA), a transcription factor, plays pivotal roles in energy metabolism across diverse tissues. Studies have demonstrated that loss of Esrra leads to fat malabsorption and resistance to diet-induced obesity. However, the reliance of these studies on germline Esrra mutants overlooks the tissue-specific implications of ESRRA in diet-induced obesity. Notably, Esrra exhibits high expression in the gastrointestinal (GI) tract relative to other tissues. Given the critical role of the GI tract in dietary lipid metabolism, this study employs mouse genetics and genomics approaches to dissect the specific impact of intestinal ESRRA along with investigating its role in diet-induced obesity. Data Transparency ChIP-seq and RNA-seq data from this publication have been deposited to GEO accession numbers GSE269824 and GSE269825, respectively. Any additional information required to reanalyze the data reported in this paper is available from the corresponding author upon request. Grant Support This research was funded by grants from the National Institutes of Health (NIH) to M.P.V. (R01DK121915 and R01DK126446). K.V. was supported by an American Heart Association pre-doctoral fellowship (906006). S.K. was supported by a Rutgers DLS Summer Undergraduate Research Fellowship. A.L. was supported by grants from the NIH grant F31DK137596 and the NIH T32 Biotechnology Training Program (GM135141). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Disclosures The authors declare no competing interests.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640181","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}

{"title":"Generation of human appetite-regulating neurons and tanycytes from stem cells","authors":"Zehra Abay-Nørgaard, Anika K Müller, Erno Hänninen, Dylan Rausch, Louise Piilgaard, Jens Bager Christensen, Sofie Peeters, Alrik L. Schörling, Alison Salvador, Viktoriia Nikulina, Yuan Li, Janko Kajtez, T. Pers, A. Kirkeby","doi":"10.1101/2024.07.11.603039","DOIUrl":"https://doi.org/10.1101/2024.07.11.603039","url":null,"abstract":"The balance between energy intake and expenditure is controlled by the hypothalamus, a small brain region characterised by high neuronal diversity. Specifically, the arcuate nucleus (ARC) and ventromedial hypothalamus (VMH) are key hypothalamic nuclei controlling appetite through behavioural response to circulating humoral signals. Yet, despite their physiological importance, the cellular and functional characteristics of this highly specialised neural region has been studied mainly in animals due to a lack of human models. Here, we fine-tuned the differentiation of human pluripotent stem cells toward the ARC and VMH hypothalamic nuclei and identified key subtype-specific progenitor markers of these subregions. We demonstrate that the timing for initiation and termination of bone morphogenetic protein (BMP) signalling is essential for controlling subregional specification of tuberal hypothalamic progenitors along the anterior-posterior axis, balancing VMH versus ARC fates. A particular population of SHH-/NKX2.1+/FGF10high/RAXhigh/TBX3high posterior tuberal progenitors was identified as the source for generation of ARC-associated agouti-related peptide (AGRP) neurons and tanycytes whilst anterior tuberal SHH+/NKX2.1+/FGF10low/RAXlow/TBX3low progenitors generated VMH phenotypes including NR5A1 neurons. Upon maturation in vitro and in xenografts, ARC-patterned progenitors gave rise to key appetite-regulating cell types including those producing AGRP, prepronociceptin (PNOC), growth hormone-releasing hormone (GHRH), thyrotropin-releasing hormone (TRH) and pro-opiomelanocortin (POMC), as well as tanycyte glial cells. Differentiated ARC cultures showed high transcriptomic similarity to the human ARC and displayed evidence of functionality by AGRP secretion and responsiveness to leptin and fibroblast growth factor 1 (FGF1). In summary, our work provides insights into the developmental lineages underlying hypothalamic subregional specification and enables access to highly characterised human ARC and VMH cultures, which will provide novel opportunities for investigating the cellular and molecular pathways triggered by obesity-associated genetic variants and weight-regulating stimuli.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"9 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640277","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}

{"title":"Importance of transcript variants in transcriptome analyses","authors":"Kevin Vo, Ryan Mohamadi, Yashica Sharma, Amelia Mohamadi, Patrick E Fields, M. A. K. Rumi","doi":"10.1101/2024.07.11.603122","DOIUrl":"https://doi.org/10.1101/2024.07.11.603122","url":null,"abstract":"RNA sequencing (RNA-Seq) has become a widely adopted genome-wide technique for investigating gene expression patterns. However, conventional RNA-Seq analyses typically rely on gene expression (GE) values that aggregate all the transcripts produced by a gene under a single identifier, overlooking the complexity of transcript variants arising from different transcription start sites and alternative splicing events. In this study, we explored the implications of neglecting transcript variants in RNA-Seq analyses. Among the 1334 transcription factor (TF) genes expressed in mouse embryonic stem (ES) or trophoblast stem (TS) cells, 652 were reported to be differentially expressed in TS cells based on GE values (365 upregulated and 287 downregulated, ≥2-fold, FDR p-value ≤0.05). Intriguingly, differential gene expression analysis revealed that of the 365 upregulated genes, 883 transcript variants were expressed, with only 174 (<20%) variants exhibiting upregulation based on transcript expression (TE) values. The remaining 709 (>80%) variants were either down-regulated or showed no significant change in expression analysis. Similarly, the 287 genes reported to be downregulated expressed 856 transcript variants, with only 153 (<20%) downregulated variants and 703 (>82%) variants that were upregulated or showed no significant changes. Additionally, the 682 TF genes that did not show significant changes between ES and TS cells (GE values < 2-fold changes and/or FDR p-values >0.05) expressed 2215 transcript variants, which included 477 (>21%) that were differentially expressed (276 upregulated and 201 downregulated, ≥2-fold, FDR p-value ≤0.05). Notably, a particular gene does not express just one protein; rather its transcript variants encode multiple proteins with distinct functional domains, including non-coding regulatory RNAs. Our findings underscore the critical necessity of considering transcript variants in RNA-Seq analyses. Doing so may enable a more precise understanding of the intricate functional and regulatory landscape of genes; ignoring the variants may result in an erroneous interpretation. Graphic Abstract Differential expression of transcription factors (TFs) between mouse embryonic stem (ES) cells and trophoblast stem (TS) cells. This graphic presentation clearly demonstrates the importance of including transcript variants during RNA sequencing (RNA-Seq) analyses. Panel A represents the conventional differential gene expression analysis approach after RNA-Seq, where all transcript reads are taken under a single gene name. Panel B takes differential gene expression analysis one step further by examining all the transcript variants that were previously hidden under the main gene name. Our results indicate that exclusive gene expression (GE) analysis inaccurately defines over 80% of the transcript expression (TE). Without analyses of all the transcript variants’ reads, we fail to uncover the functional importance of the variants and the regula","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"22 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641647","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}

{"title":"Peptipedia v2.0: A peptide sequence database and user-friendly web platform. A major update","authors":"Gabriel Cabas-Mora, Anamaría Daza, Nicole Soto-García, Valentina Garrido, Diego Alvarez, Marcelo A Navarrete, Lindybeth Sarmiento-Varón, J. H. Sepúlveda Yáñez, Mehdi D. Davari, Frederic Cadet, Á. Olivera-Nappa, Roberto Uribe-Paredes, David Medina-Ortiz","doi":"10.1101/2024.07.11.603053","DOIUrl":"https://doi.org/10.1101/2024.07.11.603053","url":null,"abstract":"In recent years, peptides have gained significant relevance due to their therapeutic properties. The surge in peptide production and synthesis has generated vast amounts of data, enabling the creation of comprehensive databases and information repositories. Advances in sequencing techniques and artificial intelligence have further accelerated the design of tailor-made peptides. However, leveraging these techniques requires versatile and continuously updated storage systems, along with tools that facilitate peptide research and the implementation of machine learning for predictive systems. This work introduces Peptipedia v2.0, one of the most comprehensive public repositories of peptides, supporting biotechnological research by simplifying peptide study and annotation. Peptipedia v2.0 has expanded its collection by over 45% with peptide sequences that have reported biological activities. The functional biological activity tree has been revised and enhanced, incorporating new categories such as cosmetic and dermatological activities, molecular binding, and anti-ageing properties. Utilizing protein language models and machine learning, more than 90 binary classification models have been trained, validated, and incorporated into Peptipedia v2.0. These models exhibit average sensitivities and specificities of 0.877 ± 0.0530 and 0.873 ±0.054, respectively, facilitating the annotation of more than 3.6 million peptide sequences with unknown biological activities, also registered in Peptipedia v2.0. Additionally, Peptipedia v2.0 introduces description tools based on structural and ontological properties and user-friendly machinelearning tools to facilitate the application of machine-learning strategies to study peptide sequences. Peptipedia v2.0 is accessible under the Creative Commons CC BY-NC-ND 4.0 license at https://peptipedia.cl/.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"83 21","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643288","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}

{"title":"Rhabdomyosarcoma fusion oncoprotein initially pioneers a neural signature in vivo","authors":"Jack Kucinski, Alexi Tallan, C. Taslim, Meng Wang, Matthew V. Cannon, Katherine M. Silvius, Benjamin Z. Stanton, Genevieve C. Kendall","doi":"10.1101/2024.07.12.603270","DOIUrl":"https://doi.org/10.1101/2024.07.12.603270","url":null,"abstract":"Fusion-positive rhabdomyosarcoma is an aggressive pediatric cancer molecularly characterized by arrested myogenesis. The defining genetic driver, PAX3::FOXO1, functions as a chimeric gain-of-function transcription factor. An incomplete understanding of PAX3::FOXO1’s in vivo epigenetic mechanisms has hindered therapeutic development. Here, we establish a PAX3::FOXO1 zebrafish injection model and semi-automated ChIP-seq normalization strategy to evaluate how PAX3::FOXO1 initially interfaces with chromatin in a developmental context. We investigated PAX3::FOXO1’s recognition of chromatin and subsequent transcriptional consequences. We find that PAX3::FOXO1 interacts with inaccessible chromatin through partial/homeobox motif recognition consistent with pioneering activity. However, PAX3::FOXO1-genome binding through a composite paired-box/homeobox motif alters chromatin accessibility and redistributes H3K27ac to activate neural transcriptional programs. We uncover neural signatures that are highly representative of clinical rhabdomyosarcoma gene expression programs that are enriched following chemotherapy. Overall, we identify partial/homeobox motif recognition as a new mode for PAX3::FOXO1 pioneer function and identify neural signatures as a potentially critical PAX3::FOXO1 tumor initiation event.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"13 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141641100","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}

{"title":"CompareM2 is a genomes-to-report pipeline for comparing microbial genomes","authors":"Carl M. Kobel, Velma T. E. Aho, Ove Øyås, Niels Nørskov-Lauritsen, Ben J. Woodcroft, Phillip B. Pope","doi":"10.1101/2024.07.12.603264","DOIUrl":"https://doi.org/10.1101/2024.07.12.603264","url":null,"abstract":"Here, we present CompareM2, a genomes-to-report pipeline for comparative analysis of bacterial and archaeal genomes derived from isolates and metagenomic assemblies. CompareM2 is easy to install and operate, and integrates community-adopted tools to perform genome quality control and annotation, taxonomic and functional predictions, as well as comparative analyses of core- and pan-genome partitions and phylogenetic relations. The central results generated via the CompareM2 workflow are emphasized in a portable dynamic report document. CompareM2 is free software and welcomes modifications and pull requests from the community on its Git repository at https://github.com/cmkobel/comparem2.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"2 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642258","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}

{"title":"Welcome to Hotel Hymenoptera: monitoring cavity-nesting bee and wasp distribution and their trophic interactions using community science and metabarcoding","authors":"Sage Handler, K. Coveny, Thomas W. A. Braukmann, N. E. Raine, Dirk Steinke","doi":"10.1101/2024.07.10.602935","DOIUrl":"https://doi.org/10.1101/2024.07.10.602935","url":null,"abstract":"Essential ecosystem services are provided by many interactions, including plant-pollinator, predator-prey, and host-parasitoid. These services support food and natural systems through pollination and pest control, however they are challenging to qualify, and previous observational studies may underestimate their complexity. The cavity nesting Hymenoptera are a good example showing all these three interactions and they can be monitored using trap nests. For this study, trap nests were installed at schools across Canada by community scientists to investigate cavity-nesting bee and wasp distributions and interactions. DNA metabarcoding was used to identify the occupants and their food sources. New bee and wasp distributions were found that might be the result of previous under-sampling or recent range expansions. Detailed bipartite and tripartite networks describing species interactions suggest some novel bee, wasp, and parasite associations. These results encourage further investigation into these interactions using molecular methods as detailed range maps and networks provide information to natural historians and conservationists alike.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"8 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141642407","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}

{"title":"Langerhans cells regulate immunity in adulthood by regulating postnatal dermal lymphatic development","authors":"JiHyun Sim, Richard Bell, Zhonghui Feng, Susan Chyou, William D Shipman, Raghu P. Kataru, Lionel Ivashkiv, Babak J. Mehrara, Theresa T. Lu","doi":"10.1101/2024.07.12.603312","DOIUrl":"https://doi.org/10.1101/2024.07.12.603312","url":null,"abstract":"The communication between skin and draining lymph nodes is crucial for well-regulated immune responses to skin insults. The skin sends antigen and other signals via lymphatic vessels to regulate lymph node activity, and regulating dermal lymphatic function is another means to control immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, mediate dermal lymphatic expansion and phenotype acquisition postnatally, a function is independent of LC entry into lymphatic vessels. This postnatal LC-lymphatic axis serves in part to control inflammatory systemic T cell responses in adulthood. Our data provide a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"76 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643101","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}

{"title":"Filtering for highly variable genes and high quality spots improves phylogenetic analysis of cancer spatial transcriptomics Visium data","authors":"Alexandra “Sasha” Gavryushkina, H. R. Pinkney, Sarah D. Diermeier, A. Gavryushkin","doi":"10.1101/2024.07.11.603166","DOIUrl":"https://doi.org/10.1101/2024.07.11.603166","url":null,"abstract":"Phylogenetic relationship of cells within tumours can help us to understand how cancer develops in space and time, iden-tify driver mutations and other evolutionary events that enable can-cer growth and spread. Numerous studies have reconstructed phylo-genies from single-cell DNA-seq data. Here we are looking into the problem of phylogenetic analysis of spatially resolved near single-cell RNA-seq data, which is a cost-efficient alternative (or complemen-tary) data source that integrates multiple sources of evolutionary information including point mutations, copy-number changes, and epimutations. Recent attempts to use such data, although promis-ing, raised many methodological challenges. Here, we explored data-preprocessing and modelling approaches for evolutionary analyses of Visium spatial transcriptomics data. We conclude that using only highly variable genes and accounting for heterogeneous RNA capture across tissue-covered spots improves the reconstructed topological relationships and influences estimated branch lengths.","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"7 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141640692","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}

{"title":"Cell-type specific binocular interactions in mouse visual thalamus","authors":"Sean P. Masterson, Govin Govindaiah, William Guido, M. E. Bickford","doi":"10.1101/2024.07.12.603141","DOIUrl":"https://doi.org/10.1101/2024.07.12.603141","url":null,"abstract":"Projections from each eye are segregated in separate domains within the dorsal lateral geniculate nucleus (dLGN). Yet, in vivo studies indicate that the activity of single dLGN neurons can be influenced by visual stimuli presented to either eye. In this study we explored whether intrinsic circuits mediate binocular interactions in the mouse dLGN. We employed dual color optogenetics in vitro to selectively activate input from each eye and recorded synaptic responses in thalamocortical (relay) cells as well as inhibitory interneurons, which have extensive dendritic arbors that are not confined to eye specific domains. While most relay cells received monocular retinal input, most interneurons received binocular retinal input; consequently, the majority of dLGN relay cells received binocular retinogeniculate-evoked inhibition. Moreover, in recordings from adjacent pairs of relay cells and interneurons, the most common relationship observed was binocular excitation of interneurons paired with binocular inhibition of adjacent relay cells. Finally, we found that dLGN interneurons are interconnected, displaying both monocular and binocular inhibition in response to retinal activation. In sum, our results indicate that geniculate interneurons provide one of the first locations where signals from the two eyes can be compared, integrated, and adjusted before being transmitted to cortex, shedding new light on the role of the thalamus in binocular vision. Highlights In vitro dual color optogenetics examined convergence of eye-specific retinal inputs to thalamocortical (relay) cells and interneurons in the dLGN The majority of relay cells receive monocular excitatory retinogeniculate input while the majority of interneurons receive binocular input Binocular relay cells are located in and around the ipsilateral patch whereas binocular interneurons are distributed throughout the dLGN The majority of relay cells receive binocular retinogeniculate-evoked inhibition dLGN interneurons are interconnected, receiving both monocular and binocular retinogeniculate-evoked inhibition","PeriodicalId":9124,"journal":{"name":"bioRxiv","volume":"66 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141643385","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}