bioRxiv : the preprint server for biology最新文献

{"title":"Lipid Transfer Proteins and PI4KIIα Initiate Nuclear p53-Phosphoinositide Signaling.","authors":"Noah D Carrillo, Mo Chen, Tianmu Wen, Poorwa Awasthi, Trevor J Wolfe, Colin Sterling, Vincent L Cryns, Richard A Anderson","doi":"10.1101/2023.05.08.539894","DOIUrl":"10.1101/2023.05.08.539894","url":null,"abstract":"<p><p>Phosphoinositide (PIP _n ) messengers are present in non-membranous regions of nuclei where they are assembled into a phosphatidylinositol (PI) 3-kinase (PI3K)/Akt pathway that is distinct from the cytosolic membrane-localized pathway. In the nuclear pathway, PI kinases/phosphatases bind the p53 tumor suppressor protein (wild-type and mutant) to generate p53-PIP _n complexes (p53-PIP _n signalosome) that activate Akt by a PI3,4,5P ₃ -dependent mechanism in non-membranous regions of the nucleus. This pathway is dependent on a source of nuclear PIP _n s that is poorly characterized. Here we report that a subset of PI transfer proteins (PITPs), which transport PI between membranes to enable membrane-localized PIP _n synthesis, also interact with p53 in the nucleus upon genotoxic stress. Class I PITPs (PITPα/β) specifically supply the PI required for the generation of p53-PIP _n complexes and subsequent signaling in the nucleus. Additionally, the PI 4-kinase PI4KIIα binds to p53 and the PITPs to catalyze the formation of p53-PI4P. p53-PI4P is then sequentially phosphorylated to synthesize p53-PIP _n complexes that regulate p53 stability, nuclear Akt activation and genotoxic stress resistance. In this way, PITPα/β and PI4KIIα bind p53 and collaborate to initiate p53-PIP _n signaling by mechanisms that require PI transfer by PITPα/β and the catalytic activity of PI4KIIα. Moreover, the identification of these critical upstream regulators of p53-PIP _n signaling point to PITPα/β and PI4KIIα as novel therapeutic targets in this pathway for diseases like cancer.</p><p><strong>Significance statement: </strong>PI transfer proteins and a PI 4-kinase initiate nuclear p53-phosphoinositide signaling in membrane-free regions to promote stress resistance.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9506084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A sub-set of guanine- and cytosine-rich genes are actively transcribed at the nuclear Lamin B1 region.","authors":"Gayan I Balasooriya, Tse-Luen Wee, David L Spector","doi":"10.1101/2023.10.28.564411","DOIUrl":"10.1101/2023.10.28.564411","url":null,"abstract":"<p><p>Chromatin organization in the mammalian cell nucleus plays a vital role in the regulation of gene expression. The lamina-associated domain at the inner nuclear membrane has been shown to harbor heterochromatin, while the nuclear interior has been shown to contain most of the euchromatin. Here, we show that a sub-set of actively transcribing genes, marked by RNA Pol II pSer2, are associated with Lamin B1 at the inner nuclear envelope in mouse embryonic stem cells (mESCs) and the number of genes proportionally increases upon <i>in vitro</i> differentiation of mESC to olfactory precursor cells. These nuclear periphery-associated actively transcribing genes primarily represent housekeeping genes, and their gene bodies are significantly enriched with guanine and cytosine compared to genes actively transcribed at the nuclear interior. We found the promoters of these gene's to also be significantly enriched with guanine and to be predominantly regulated by zinc finger protein transcription factors. We provide evidence supporting the emerging notion that the Lamin B1 region is not solely transcriptionally silent.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10634887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92157604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysosomal proteomics reveals mechanisms of neuronal apoE4-associated lysosomal dysfunction.","authors":"Einar K Krogsaeter, Justin McKetney, Leopoldo Valiente-Banuet, Angelica Marquez, Alexandra Willis, Zeynep Cakir, Erica Stevenson, Gwendolyn M Jang, Antara Rao, Emmy Li, Anton Zhou, Anjani Attili, Timothy S Chang, Martin Kampmann, Yadong Huang, Nevan J Krogan, Danielle L Swaney","doi":"10.1101/2023.10.02.560519","DOIUrl":"10.1101/2023.10.02.560519","url":null,"abstract":"<p><p>ApoE4 is the primary risk factor for Alzheimer Disease (AD). Early AD pathological events first affect the neuronal endolysosomal system, which in turn causes neuronal protein aggregation and cell death. Despite the crucial influence of lysosomes upon AD pathophysiology, and that apoE4 localizes to lysosomes, the influence of apoE4 on lysosomal function remains unexplored. We find that expression of apoE4 in neuronal cell lines results in lysosomal alkalinization and impaired lysosomal function. To identify driving factors for these defects, we performed quantitative lysosomal proteome profiling. This revealed that apoE4 expression results in differential regulation of numerous lysosomal proteins, correlating with apoE allele status and disease severity in AD brains. In particular, apoE4 expression results in the depletion of lysosomal Lgals3bp and the accumulation of lysosomal Tmed5. We additionally validated that these lysosomal protein changes can be targeted to modulate lysosomal function. Taken together, this work thereby reveals that apoE4 causes widespread lysosomal defects through remodeling the lysosomal proteome, with the lysosomal Tmed5 accumulation and Lgals3bp depletion manifesting as lysosomal alkalinization in apoE4 neurons.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592882/pdf/nihpp-2023.10.02.560519v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Hierarchy of the Human Neocortex from Cradle to Grave.","authors":"Hoyt Patrick Taylor, Khoi Minh Huynh, Kim-Han Thung, Guoye Lin, Wenjiao Lyu, Weili Lin, Sahar Ahmad, Pew-Thian Yap","doi":"10.1101/2024.06.14.599109","DOIUrl":"10.1101/2024.06.14.599109","url":null,"abstract":"<p><p>Recent evidence indicates that the organization of the human neocortex is underpinned by smooth spatial gradients of functional connectivity (FC). These gradients provide crucial insight into the relationship between the brain's topographic organization and the texture of human cognition. However, no studies to date have charted how intrinsic FC gradient architecture develops across the entire human lifespan. In this work, we model developmental trajectories of the three primary gradients of FC using a large, high-quality, and temporally-dense functional MRI dataset spanning from birth to 100 years of age. The gradient axes, denoted as sensorimotor-association (SA), visual-somatosensory (VS), and modulation-representation (MR), encode crucial hierarchical organizing principles of the brain in development and aging. By tracking their development throughout the human lifespan, we provide the first ever comprehensive low-dimensional normative reference of global FC hierarchical architecture. We observe significant age-related changes in global network features, with global markers of hierarchical organization increasing from birth to early adulthood and decreasing thereafter. During infancy and early childhood, FC organization is shaped by primary sensory processing, dense short-range connectivity, and immature association and control hierarchies. Functional differentiation of transmodal systems supported by long-range coupling drives a convergence toward adult-like FC organization during late childhood, while adolescence and early adulthood are marked by the expansion and refinement of SA and MR hierarchies. While gradient topographies remain stable during late adulthood and aging, we observe decreases in global gradient measures of FC differentiation and complexity from 30 to 100 years. Examining cortical microstructure gradients alongside our functional gradients, we observed that structure-function gradient coupling undergoes differential lifespan trajectories across multiple gradient axes.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11195193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the effect of CRISPR-Cas9-based epigenome editing.","authors":"Sanjit Singh Batra, Alan Cabrera, Jeffrey P Spence, Jacob Goell, Selvalakshmi S Anand, Isaac B Hilton, Yun S Song","doi":"10.1101/2023.10.03.560674","DOIUrl":"10.1101/2023.10.03.560674","url":null,"abstract":"<p><p>Epigenetic regulation orchestrates mammalian transcription, but functional links between them remain elusive. To tackle this problem, we use epigenomic and transcriptomic data from 13 ENCODE cell types to train machine learning models to predict gene expression from histone post-translational modifications (PTMs), achieving transcriptome-wide correlations of ~ 0.70 - 0.79 for most cell types. Our models recapitulate known associations between histone PTMs and expression patterns, including predicting that acetylation of histone subunit H3 lysine residue 27 (H3K27ac) near the transcription start site (TSS) significantly increases expression levels. To validate this prediction experimentally and investigate how natural vs. engineered deposition of H3K27ac might differentially affect expression, we apply the synthetic dCas9-p300 histone acetyltransferase system to 8 genes in the HEK293T cell line and to 5 genes in the K562 cell line. Further, to facilitate model building, we perform MNase-seq to map genome-wide nucleosome occupancy levels in HEK293T. We observe that our models perform well in accurately ranking relative fold-changes among genes in response to the dCas9-p300 system; however, their ability to rank fold-changes within individual genes is noticeably diminished compared to predicting expression across cell types from their native epigenetic signatures. Our findings highlight the need for more comprehensive genome-scale epigenome editing datasets, better understanding of the actual modifications made by epigenome editing tools, and improved causal models that transfer better from endogenous cellular measurements to perturbation experiments. Together these improvements would facilitate the ability to understand and predictably control the dynamic human epigenome with consequences for human health.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10592942/pdf/nihpp-2023.10.03.560674v1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49694644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-plateau force-extension curves of long double-stranded DNA molecules.","authors":"Alexander Y Afanasyev, Alexey V Onufriev","doi":"10.1101/2023.03.12.532320","DOIUrl":"10.1101/2023.03.12.532320","url":null,"abstract":"<p><p>When highly stretched, double-stranded DNA exhibits a plateau region in its force-extension curve. Using a bead-spring coarse-grained dynamic model based on a non-convex potential, we predict that a long double-stranded DNA fragment made of several consecutive segments with substantially different plateau force values for each segment will exhibit multiple distinct plateau regions in the force-extension curve under physiologically relevant solvent conditions. For example, a long composite double-stranded (ds) DNA fragment consisting of two equal-length segments characterized by two different plateau force values, such as the poly(dA-dT)-poly(dG-dC) fragment, is predicted to exhibit two distinct plateau regions in its force-extension curve; a long composite dsDNA fragment consisting of three segments having three different plateau force values is predicted to have three distinct plateau regions. The formation of mixed states of slightly and highly stretched DNA, co-existing with macroscopically distinct phases of uniformly stretched DNA is also predicted. When one of the segments overstretches, the extensions of the segments can differ drastically. For example, for the poly(dA-dT)-poly(dG-dC) composite fragment, in the middle of the first plateau, 96.7 % of the total extension of the fragment (relative to <math> <mrow><msub><mi>L</mi> <mi>x</mi></msub> <mo>/</mo> <msub><mi>L</mi> <mn>0</mn></msub> <mo>≈</mo> <mn>1.0</mn></mrow> </math> ) comes from the poly(dA-dT) segment, while only 3.3 % of it comes from the poly(dG-dC) segment. The order of the segments has little effect on the force-extension curve or the distribution of conformational states. We speculate that the distinct structural states of stretched double-stranded DNA may have functional importance. For example, these states may modulate, in a sequence-dependent manner, the rate of double-stranded DNA processing by key cellular machines.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888220/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73938937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic representation of multidimensional object properties in the human brain.","authors":"Lina Teichmann, Martin N Hebart, Chris I Baker","doi":"10.1101/2023.09.08.556679","DOIUrl":"10.1101/2023.09.08.556679","url":null,"abstract":"<p><p>Our visual world consists of an immense number of unique objects and yet, we are easily able to identify, distinguish, interact, and reason about the things we see within a few hundred milliseconds. This requires that we integrate and focus on a wide array of object properties to support diverse behavioral goals. In the current study, we used a large-scale and comprehensively sampled stimulus set and developed an analysis approach to determine if we could capture how rich, multidimensional object representations unfold over time in the human brain. We modelled time-resolved MEG signals evoked by viewing single presentations of tens of thousands of object images based on millions of behavioral judgments. Extracting behavior-derived object dimensions from similarity judgments, we developed a data-driven approach to guide our understanding of the neural representation of the object space and found that every dimension is reflected in the neural signal. Studying the temporal profiles for different object dimensions we found that the time courses fell into two broad types, with either a distinct and early peak (~125 ms) or a slow rise to a late peak (~300 ms). Further, early effects were stable across participants, in contrast to later effects which showed more variability, suggesting that early peaks may carry stimulus-specific and later peaks more participant-specific information. Dimensions with early peaks appeared to be primarily visual dimensions and those with later peaks more conceptual, suggesting that conceptual representations are more variable across people. Together, these data provide a comprehensive account of how behavior-derived object properties unfold in the human brain and form the basis for the rich nature of object vision.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7d/1e/nihpp-2023.09.08.556679v2.PMC10515754.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41170855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional Identification of Language-Responsive Channels in Individual Participants in MEG Investigations.","authors":"Mathias Huybrechts, Rose Bruffaerts, Alvince Pongos, Cory Shain, Benjamin Lipkin, Matthew Siegelman, Vincent Wens, Martin Sjøgård, Idan Blank, Serge Goldman, Xavier De Tiège, Evelina Fedorenko","doi":"10.1101/2023.03.23.533424","DOIUrl":"10.1101/2023.03.23.533424","url":null,"abstract":"<p><p>Making meaningful inferences about the functional architecture of the language system requires the ability to refer to the same neural units across individuals and studies. Traditional brain imaging approaches align and average brains together in a common space. However, lateral frontal and temporal cortices, where the language system resides, is characterized by high structural and functional inter-individual variability, which reduces the sensitivity and functional resolution of group-averaging analyses. This issue is compounded by the fact that language areas lay in close proximity to regions of other large-scale networks with different functional profiles. A solution inspired by visual neuroscience is to identify language areas functionally in each individual brain using a 'localizer' task (e.g., a language comprehension task). This approach has proven productive in fMRI, yielding a number of robust and replicable findings about the language system. Here, we extend this approach to MEG. Across two experiments (one in Dutch speakers, n=19; one in English speakers, n=23), we examined neural responses to the processing of sentences and a control condition (nonword sequences). In both the time and frequency domains, we demonstrated that the topography of neural responses to language is spatially stable within individuals but varies across individuals. Consequently, analyses that take this inter-individual variability into account are characterized by greater sensitivity, compared to the group-level analyses. In summary, similar to fMRI, functional identification within individuals yields benefits in MEG, thus opening the door to future investigations of language processing including questions where whole-brain coverage and temporal resolution are both critical.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/98/e7/nihpp-2023.03.23.533424v1.PMC10055362.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9650999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Widespread epistasis shapes RNA Polymerase II active site function and evolution.","authors":"Bingbing Duan, Chenxi Qiu, Sing-Hoi Sze, Craig Kaplan","doi":"10.1101/2023.02.27.530048","DOIUrl":"10.1101/2023.02.27.530048","url":null,"abstract":"<p><p>Multi-subunit RNA Polymerases (msRNAPs) are responsible for transcription in all kingdoms of life. These enzymes rely on dynamic, highly conserved active site domains such as the so-called \"trigger loop\" (TL) to accomplish steps in the transcription cycle. Mutations in the RNA polymerase II (Pol II) TL confer a spectrum of biochemical and genetic phenotypes that suggest two main classes, which decrease or increase catalysis or other nucleotide addition cycle (NAC) events. The Pol II active site relies on networks of residue interactions to function and mutations likely perturb these networks in ways that may alter mechanisms. We have undertaken a structural genetics approach to reveal residue interactions within and surrounding the Pol II TL - determining its \"interaction landscape\" - by deep mutational scanning in <i>Saccharomyces cerevisiae</i> Pol II. This analysis reveals connections between TL residues and surrounding domains, demonstrating that TL function is tightly coupled to its specific enzyme context.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/5e/78/nihpp-2023.02.27.530048v2.PMC10002619.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9307975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WITHDRAWN: <i>MHC-B</i> Diversity and Signs of Respiratory Illness in Wild, East African Chimpanzees ( <i>Pan troglodytes schweinfurthii</i> ).","authors":"S R Phillips","doi":"10.1101/2023.08.02.551731","DOIUrl":"10.1101/2023.08.02.551731","url":null,"abstract":"<p><p>bioRxiv has withdrawn this preprint following a formal investigation by the University of New Mexico Office of Research Integrity and Compliance.</p>","PeriodicalId":72407,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10418158/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9991210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}