eLifePub Date : 2025-07-17DOI: 10.7554/eLife.102701
Bjorn Gylemo, Maike Bensberg, Colm E Nestor
{"title":"A whole-organism landscape of X-inactivation in humans.","authors":"Bjorn Gylemo, Maike Bensberg, Colm E Nestor","doi":"10.7554/eLife.102701","DOIUrl":"https://doi.org/10.7554/eLife.102701","url":null,"abstract":"<p><p>As females are mosaic for X-inactivation, direct determination of X-linked allelic expression in bulk tissues is typically unfeasible. Using females that are non-mosaic (completely skewed) for X-inactivation (nmXCI) has proven a powerful and natural genetic system for profiling X-inactivation in humans. By combining allele-resolution data for one previously reported and two newly identified nmXCI females, we directly determined X-inactivation status of 380 X-linked genes across 30 normal tissues, including 198 genes for which XCI status is directly determined for the first time. Our findings represent a substantial advance in our understanding of human X-inactivation and will serve as a reference for dissecting the genetic origin of sex bias in human traits. In addition, our study reveals nmXCI as a common feature of the human female population, with profound consequences for the penetrance and expressivity of X-linked traits in humans.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-17DOI: 10.7554/eLife.105788
Yi Wu, Weilin Guo, Haoyue Kuang, Xiaohai Wu, Thi Huong Trinh, Yuexin Wang, Shizheng Zhao, Zilong Wen, Tao Yu
{"title":"Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals.","authors":"Yi Wu, Weilin Guo, Haoyue Kuang, Xiaohai Wu, Thi Huong Trinh, Yuexin Wang, Shizheng Zhao, Zilong Wen, Tao Yu","doi":"10.7554/eLife.105788","DOIUrl":"https://doi.org/10.7554/eLife.105788","url":null,"abstract":"<p><p>Microglia are brain-resident macrophages playing pivotal roles in central nervous system (CNS) development and homeostasis. Yet, the cellular and molecular basis governing microglia maintenance remains largely unknown. Here, by utilizing a visible conditional knockout allele of <i>pu.1/spi1b</i> gene (the master regulator for microglia/macrophage lineage development) to generate mosaic microglia populations in adult zebrafish, we show that while <i>pu.1</i>-deficient microglia are immediately viable, they are less competitive, and chronically eliminated through Tp53-mediated cell competition. Interestingly, when conditionally inactivating Pu.1 in adult <i>spi-b</i> (the orthologue of mouse <i>Spi-b</i>) null mutants, microglia are rapidly depleted via apoptosis, suggesting that Pu.1 and Spi-b regulate microglia maintenance in a dosage-dependent manner. The dosage-dependent regulation of microglia maintenance by PU.1/SPI1 is evolutionarily conserved in mice, as shown by conditionally inactivating single and both <i>Spi1</i> alleles in microglia, respectively. Collectively, our study reveals the conserved cellular and molecular mechanisms controlling microglia turnover and maintenance in teleosts and mammals.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-17DOI: 10.7554/eLife.105565
Yafan Zhang, Irene Silvernail, Zhuyang Lin, Xingcheng Lin
{"title":"Interpretable protein-DNA interactions captured by structure-sequence optimization.","authors":"Yafan Zhang, Irene Silvernail, Zhuyang Lin, Xingcheng Lin","doi":"10.7554/eLife.105565","DOIUrl":"https://doi.org/10.7554/eLife.105565","url":null,"abstract":"<p><p>Sequence-specific DNA recognition underlies essential processes in gene regulation, yet methods for simultaneous predictions of genomic DNA recognition sites and their binding affinity remain lacking. Here, we present the Interpretable protein-DNA Energy Associative (IDEA) model, a residue-level, interpretable biophysical model capable of predicting binding sites and affinities of DNA-binding proteins. By fusing structures and sequences of known protein-DNA complexes into an optimized energy model, IDEA enables direct interpretation of physicochemical interactions among individual amino acids and nucleotides. We demonstrate that this energy model can accurately predict DNA recognition sites and their binding strengths across various protein families. Additionally, the IDEA model is integrated into a coarse-grained simulation framework that quantitatively captures the absolute protein-DNA binding free energies. Overall, IDEA provides an integrated computational platform that alleviates experimental costs and biases in assessing DNA recognition and can be utilized for mechanistic studies of various DNA-recognition processes.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-17DOI: 10.7554/eLife.104255
Leonid Peshkin, Enrico Maria Daldello, Elizabeth S Van Itallie, Matthew Sonnett, Johannes Kreuzer, Wilhelm Haas, Marc W Kirschner, Catherine Jessus
{"title":"Decoding protein phosphorylation during oocyte meiotic divisions using phosphoproteomics.","authors":"Leonid Peshkin, Enrico Maria Daldello, Elizabeth S Van Itallie, Matthew Sonnett, Johannes Kreuzer, Wilhelm Haas, Marc W Kirschner, Catherine Jessus","doi":"10.7554/eLife.104255","DOIUrl":"https://doi.org/10.7554/eLife.104255","url":null,"abstract":"<p><p>Oocyte meiotic divisions represent a critical process in sexual reproduction, as a diploid non-dividing oocyte is transformed into a haploid fertilizable egg, as a prelude for the subsequent embryonic divisions and differentiation. Although cell differentiation and proliferation are governed by transcription, oocyte maturation and early embryonic divisions depend entirely on changes in protein abundance and post-translational modifications. Here, we analyze the abundance and phosphorylation of proteins during <i>Xenopus</i> oocyte meiotic maturation. We reveal significant shifts in protein stability, related to spindle assembly, DNA replication, and RNA-binding. Our analysis pinpoints broad changes in phosphorylation correlating with key cytological meiotic milestones, noteworthy changes in membrane trafficking, nuclear envelope disassembly, and modifications in microtubule dynamics. Additionally, specific phosphorylation events target regulators of protein translation, Cdk1 and the Mos/MAPK pathway, thereby providing insight into the dynamics of Cdk1 activity, as related to the meiotic cell cycle. This study sheds light on the orchestration of protein dynamics and phosphorylation events during oocyte meiotic divisions, providing a rich resource for understanding the molecular pathways orchestrating meiotic progression in the frog, and most likely applicable to other vertebrate species.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-17DOI: 10.7554/eLife.104118
Ronja Bigge, Rebecca Grittner, Anna Lisa Stöckl
{"title":"Integration of parallel pathways for flight control in a hawkmoth reflects prevalence and relevance of natural visual cues.","authors":"Ronja Bigge, Rebecca Grittner, Anna Lisa Stöckl","doi":"10.7554/eLife.104118","DOIUrl":"https://doi.org/10.7554/eLife.104118","url":null,"abstract":"<p><p>An animal's behaviour is the result of multiple neural pathways acting in parallel, receiving information across and within sensory modalities at the same time. How these pathways are integrated, particularly when their individual outputs are in conflict, is key to understanding complex natural behaviours. We investigated this question in the visually guided flight of the hummingbird hawkmoth <i>Macroglossum stellatarum</i>. These insects were recently shown to partition their visual field, using ventrolateral optic flow cues to guide their flight like most insects, while the same stimuli in the dorsal visual field evoke a novel directional response. Using behavioural experiments which set the two pathways into conflict, we tested whether and how the ventrolateral and dorsal pathway integrate to guide hawkmoth flight. Combined with environmental imaging, we demonstrate that the partitioning of the visual field followed the prevalence of visual cues in the hawkmoths' natural habitats, while the integration hierarchy of the two pathways matched the relevance of these cues for the animals' flight safety, rather than their magnitude in the experimental setup or in natural habitats. These results provide new mechanistic insights into the vision-based flight control of insects and link these to their natural context. We anticipate our findings to be the starting point for comparative investigations into parallel pathways for flight guidance in insects from differently structured natural habitats.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-17DOI: 10.7554/eLife.100722
Rajae Talbi, Todd L Stincic, Kaitlin Ferrari, Choi Ji Hae, Karol Walec, Elizabeth Medve, Achi Gerutshang, Silvia Leon, Elizabeth A McCarthy, Oline K Rønnekleiv, Martin J Kelly, Victor M Navarro
{"title":"POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons.","authors":"Rajae Talbi, Todd L Stincic, Kaitlin Ferrari, Choi Ji Hae, Karol Walec, Elizabeth Medve, Achi Gerutshang, Silvia Leon, Elizabeth A McCarthy, Oline K Rønnekleiv, Martin J Kelly, Victor M Navarro","doi":"10.7554/eLife.100722","DOIUrl":"https://doi.org/10.7554/eLife.100722","url":null,"abstract":"<p><p>Inactivating mutations in the melanocortin 4 receptor (<i>MC4R</i>) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of Mc4r KO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations: the Kiss1<sup>ARH</sup> neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1<sup>AVPV/PeN</sup> neurons controlling the preovulatory luteinizing hormone (LH) surge. Here, we show that <i>Mc4r</i> expressed in Kiss1 neurons regulates fertility in females. In vivo, deletion of <i>Mc4r</i> from Kiss1 neurons in female mice replicates the reproductive impairments of Mc4r KO mice without inducing obesity. Conversely, re-insertion of <i>Mc4r</i> in Kiss1 neurons of Mc4r null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of Mc4r on Kiss1<sup>ARH</sup> versus Kiss1<sup>AVPV/PeN</sup> neurons and show that Mc4r activation excites Kiss1<sup>ARH</sup> neurons through direct synaptic actions. In contrast, Kiss1<sup>AVPV/PeN</sup> neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1<sup>AVPV/PeN</sup> neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMC<sup>ARH</sup> neurons acting through MC4R directly regulate reproductive function in females by stimulating the 'pulse generator' activity of Kiss1<sup>ARH</sup> neurons and restricting the activation of Kiss1<sup>AVPV/PeN</sup> neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-17DOI: 10.7554/eLife.108116
Estelle Grundy, Michael Udvardi
{"title":"How plants pick their friends.","authors":"Estelle Grundy, Michael Udvardi","doi":"10.7554/eLife.108116","DOIUrl":"https://doi.org/10.7554/eLife.108116","url":null,"abstract":"<p><p>A protein called RIN4 has a central role in helping legumes such as soybean and the bacteria rhizobia to develop a mutually beneficial relationship.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-16DOI: 10.7554/eLife.102858
Yiyang Ye, Qirun Wang, Jie Lin
{"title":"Physical constraints and biological regulations underlie universal osmoresponses.","authors":"Yiyang Ye, Qirun Wang, Jie Lin","doi":"10.7554/eLife.102858","DOIUrl":"10.7554/eLife.102858","url":null,"abstract":"<p><p>Microorganisms constantly transition between environments with dramatically different external osmolarities. However, theories of microbial osmoresponse integrating physical constraints and biological regulations are lacking. Here, we propose such a theory, utilizing the separation of timescales for passive responses and active regulations. We demonstrate that regulations of osmolyte production and cell-wall synthesis assist cells in coping with intracellular crowding effects and adapting to a broad range of external osmolarity. Furthermore, we predict a threshold value above which cells cannot grow, ubiquitous across bacteria and yeast. Intriguingly, the theory predicts a dramatic speedup of cell growth after an abrupt decrease in external osmolarity due to cell-wall synthesis regulation. Our theory rationalizes the unusually fast growth observed in fission yeast after an oscillatory osmotic perturbation, and the predicted growth rate peaks match quantitatively with experimental measurements. Our study reveals the physical basis of osmoresponse, yielding far-reaching implications for microbial physiology.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The myeloid cell-driven transdifferentiation of endothelial cells into pericytes promotes the restoration of BBB function and brain self-repair after stroke.","authors":"Tingbo Li, Ling Yang, Jiaqi Tu, Yufan Hao, Zhu Zhu, Yingjie Xiong, Qingzhu Gao, Lili Zhou, Guanglei Xie, Dongdong Zhang, Xuzhao Li, Yuxiao Jin, Yiyi Zhang, Bingrui Zhao, Nan Li, Xi Wang, Jie-Min Jia","doi":"10.7554/eLife.105593","DOIUrl":"https://doi.org/10.7554/eLife.105593","url":null,"abstract":"<p><p>Ischemic stroke, one of the leading causes of death in the world, is accompanied by the dysfunction of the blood-brain barrier (BBB), which aggravates neuron damage. However, the mechanisms underlying the restoration of BBB in the chronic stage after stroke remain unclear. Here, pericyte pool alterations and their consequences for BBB integrity and brain recovery were analyzed in the C57BL/6 mice stroke model. Lineage tracing, RNA-seq, and immunofluorescence staining revealed endothelial cell (EC) transdifferentiation into pericytes (E-pericytes) in C57BL/6 mice after stroke. E-pericytes depletion by diphtheria toxin A (DTA) aggravated BBB leakage and exacerbated neurological deficits in the MCAO model. The myeloid cell-driven transdifferentiation of ECs into pericytes accelerated BBB restoration and brain self-repair after stroke via endothelial-mesenchymal transformation (EndoMT). Decreasing the number of E-pericytes by specific knockout of the <i>Tgfbr2</i> gene in ECs also aggravated BBB leakage and exacerbated neurological deficits. EC-specific overexpression of the <i>Tgfbr2</i> gene promoting E-pericytes transdifferentiation reduced BBB leakage and exerted neuroprotective effects. Deciphering the mechanism by which E-pericytes coordinate post-stroke recovery may reveal a novel therapeutic opportunity.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2025-07-16DOI: 10.7554/eLife.91915
George Dimitriadis, Ella Svahn, Andrew F MacAskill, Athena Akrami
{"title":"Heron, a Knowledge Graph editor for intuitive implementation of Python-based experimental pipelines.","authors":"George Dimitriadis, Ella Svahn, Andrew F MacAskill, Athena Akrami","doi":"10.7554/eLife.91915","DOIUrl":"https://doi.org/10.7554/eLife.91915","url":null,"abstract":"<p><p>To realise a research project, experimenters face conflicting design and implementation choices across hardware and software. These include balancing ease of implementation - time, expertise, and resources - against future flexibility, the number of opaque (black box) components and reproducibility. To address this, we present Heron, a Python-based platform for constructing and running experimental and data analysis pipelines. Heron allows researchers to design experiments according to their own mental schemata, represented as a Knowledge Graph - a structure that mirrors the logical flow of an experiment. This approach speeds up implementation (and subsequent updates), while minimising black box components, increasing transparency and reproducibility. Heron supports the integration of software and hardware combinations that are otherwise too complex or costly, making it especially useful in experimental sciences with a large number of interconnected components such as robotics, neuroscience, behavioural sciences, physics, chemistry, and environmental sciences. Unlike visual-only tools, Heron combines full control (of instrument and software combinations) and flexibility with the ease of high-level programming and Graphical User Interfaces. It assumes intermediate Python proficiency and offers a clean, modular code base that encourages documentation and reuse. By removing inaccessible technical barriers, Heron enables researchers without formal engineering backgrounds to construct sophisticated, reliable and reproducible experimental setups - bridging the gap between scientific creativity and technical implementation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}