Biology subjects

Li, D.

Publications and source records attributed to Li, D..

At least 271 records · Page 15Linked to original sources

bioRxiv2024

Comparative Analysis of Human-Chimpanzee Divergence in Brain Connectivity and its Genetic Underpinnings

Chimpanzees (Pan troglodytes) are humans closest living relatives, making them the most directly relevant comparison point for understanding human brain evolution. Zeroing in on the differences in brain connectivity between humans and chimpanzees can provide key insights into the specific evolutionary changes that might have occured along the human lineage. However, conducting comparisons of brain connectivity between humans and chimpanzees remains challenging, as cross-species brain atlases established within the same framework are currently lacking. Without the availability of cross-species brain atlases, the region-wise connectivity patterns between humans and chimpanzees cannot be directly compared. To address this gap, we built the first Chimpanzee Brainnetome Atlas (ChimpBNA) by following a well-established connectivity-based parcellation framework. Leveraging this new resource, we found substantial divergence in connectivity patterns across most association cortices, notably in the lateral temporal and dorsolateral prefrontal cortex between the two species. Intriguingly, these patterns significantly deviate from the patterns of cortical expansion observed in humans compared to chimpanzees. Additionally, we identified regions displaying connectional asymmetries that differed between species, likely resulting from evolutionary divergence. Genes associated with these divergent connectivities were found to be enriched in cell types crucial for cortical projection circuits and synapse formation. These genes exhibited more pronounced differences in expression patterns in regions with higher connectivity divergence, suggesting a potential foundation for brain connectivity evolution. Therefore, our study not only provides a fine-scale brain atlas of chimpanzees but also highlights the connectivity divergence between humans and chimpanzees in a more rigorous and comparative manner and suggests potential genetic correlates for the observed divergence in brain connectivity patterns between the two species. This can help us better understand the origins and development of uniquely human cognitive capabilities.

neuroscience↗

bioRxiv2024

CAMSAP3 Forms Dimers via its lapha-helix Domain that Directly Stabilize Non-centrosomal Microtubule Minus Ends

Microtubules are vital components of the cytoskeleton. Their plus ends are dynamic and respond to changes in cell morphology, while the minus ends are stable and serve a crucial role in microtubule seeding and maintaining spatial organization. In mammalian cells, the calmodulin-regulated spectrin-associated proteins (CAMSAPs), play a key role in directly regulating the dynamics of non-centrosomal microtubules minus ends. However, the molecular mechanisms are not yet fully understood. Our study reveals that CAMSAP3 forms dimers through its C-terminal -helix; this dimerization not only enhances the microtubule-binding affinity of the CKK domain but also enables the CKK domain to regulate the dynamics of microtubules. Furthermore, CAMSAP3 also specializes in decorating at the minus end of microtubules through the combined action of the microtubule-binding domain (MBD) and the C-terminal -helix, thereby achieving dynamic regulation of the minus ends of microtubules. These findings are crucial for advancing our understanding and treatment of diseases associated with non-centrosomal microtubules. SignificanceOur study reveals the molecular mechanism of how CAMSAP3, a key regulator of non-centrosomal microtubule dynamics, directly regulates the dynamics of non-centrosomal microtubule minus ends through CKK domain. CAMSAP3 forms dimers through its C-terminal -helix, which enhances the CKK domain of CAMSAP3 binding to microtubule minus ends and confers stability of them. This finding is not limited to CAMSAP3, but can also be applied to the understanding of the regulation of non-centrosomal microtubule minus end stability by CAMSAP family proteins. Our findings deepen our comprehension of cellular structure and function, offering insights into the role of microtubules in cellular integrity and disease. This study fills a significant knowledge gap and lays the foundation for future research into the complex balance of microtubule dynamics required for cellular health and disease prevention.

cell biology↗

bioRxiv2024

Fast adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging

Lattice light-sheet microscopy (LLSM) provides a crucial observation window into intra- and inter-cellular physiology of living specimens with high speed and low phototoxicity, however, at the diffraction-limited resolution or anisotropic super-resolution with structured illumination. Here we present the meta-learning-empowered reflective lattice light-sheet virtual structured illumination microscopy (Meta-rLLS-VSIM), which instantly upgrades LLSM to a near-isotropic super resolution of [~]120-nm laterally and [~]160-nm axially, more than twofold improvement in each dimension, without any modification of the optical system or sacrifice of other imaging metrics. Moreover, to alleviate the tremendous demands on training data and time necessitated by existing deep-learning (DL) methods, we devised an adaptive online training approach by synergizing the front-end imaging system and back-end meta-learning framework, which reduced the total time for data acquisition and model training down to tens of seconds. With this method, a new model can be well-trained with tenfold less data and three orders of magnitude less time than current standard supervised learning. We demonstrate the versatile functionalities of Meta-rLLS-VSIM by imaging a variety of bioprocesses with ultrahigh spatiotemporal resolution for long duration of hundreds of multi-color volumes, characterizing the dynamic regulation of contractile ring filaments during mitosis and the growth of pollen tubes, and delineating the nanoscale distributions, dispersion, and interaction pattern of multiple organelles in embryos and eukaryotic cells.

biophysics↗

bioRxiv2024

Investigating spatial dynamics in spatial omics data with StarTrail

Spatial omics technologies revolutionize our view of biological processes within tissues. However, existing methods fail to capture localized, sharp changes characteristic of critical events (e.g. tumor development). Here, we present StarTrail, a novel gradient based method that powerfully defines rapidly changing regions and detects "cliff genes", genes exhibiting drastic expression changes at highly localized or disjoint boundaries. StarTrail, the first to leverage spatial gradients for spatial omics data, also quantifies directional dynamics. Across multiple datasets, StarTrail accurately delineates boundaries (e.g., brain layers, tumor-immune boundaries), and detects cliff genes that may regulate molecular crosstalk at these biologically relevant boundaries but are missed by existing methods. For instance, StarTrail precisely pinpointed the cancer-immune interface in a HER2+ breast cancer dataset, unveiled key cliff genes including a potential prognostic biomarker IGSF3, highlighting NK-, B-cell mediated immunity, and B cell receptor signaling pathways missed by all spatial variable gene methods attempted. StarTrail, filling important gaps in current literature, enables deeper insights into tissue spatial architecture.

genetics↗

bioRxiv2024

Intestinal microbiome dysbiosis increases Mycobacteria pulmonary colonization in mice by regulating the Nos2-associated pathways

AbstractIncreasing researches reveal gut microbiota was associated with the development of tuberculosis. How to prevent or reduce Mycobacterium tuberculosis colonization in the lungs is a key measure to prevent tuberculosis. However, the data on gut microbiota preventing Mycobacterium colonization in the lungs were scarce. Here, we established the clindamycin-inducing intestinal microbiome dysbiosis and fecal microbial transplantation models in mice to identify gut microbiotas effect on Mycobacteriums colonization in the mouse lungs and explore its potential mechanisms. The results showed that clindamycin treatment altered the diversity and composition of the intestinal bacterial and fungal microbiome, weakened the trans-kingdom network interactions between bacteria and fungi, and induced gut microbiome dysbiosis in the mice. Gut microbiota dysbiosis increases intestinal permeability and enhances the susceptibility of Mycobacterium colonization in the lungs of mice. The potential mechanisms were gut microbiota dysbiosis altered the lung transcriptome and increased Nos2 expression through the "gut-lung axis". Nos2 high expression disrupts the intracellular antimicrobial and anti-inflammatory environment by increasing the concentration of NO, decreasing the levels of ROS and Defb1 in the cells, and resulting in promoting Mycobacteria colonization in the lungs of mice. The present study raises a potential strategy for reducing the risks of Mycobacteria infections and transmission by regulating the gut microbiome balance.

microbiology↗

bioRxiv2024

Evolutionary analysis of paired box gene family and biological function exploration of Lr.Pax7 in lamprey (Lethenteron reissneri)

The Pax(paired box)gene family comprises highly conserved transcription factors that play a crucial regulatory role in embryonic development, tissue morphogenesis, and cell differentiation. The gene family comprises of nine members, namely Pax1 to Pax9, each exhibiting distinct functionalities and expression patterns. Among the members of the Pax family, Pax7 is particularly involved in key regulatory functions related to skeletal muscle development and satellite cell biology in vertebrates. However, the precise role of Pax7 and its downstream targets in jawless vertebrates such as lamprey remains relatively understudied. Therefore, investigating the expression and function of lampreys Pax genes holds significant value as a model organism for understanding developmental processes, evolution, and interactions with other vertebrates. In this study, we identified Pax7 in Lethentero reissneri and multiple bioinformatics analyses suggested that it may represent the ancestral gene of the Pax7 shared among higher vertebrates. To further elucidate the function and regulatory mechanism of Pax7, we performed transcriptome sequencing analysis after silencing Lr.Pax7 expression which revealed alterations in metabolic processes along with associated genes(Plcy,Jagged2,Hes,Myod,Frizzled2,etc) involved in various immune pathways(Notch, Wnt, IL-17, TNF, etc), myogenesis process, adipocyte formation process consistent with those observed in higher vertebrates. Comparative studies between lamprey and high vertebrates could provide valuable insight into understanding the functional role of Pax7 and its downstream targets across diverse biological process as well as disease states.

evolutionary biology↗

bioRxiv2024

Time-lapse Image Super-resolution Neural Network with Reliable Confidence Evaluation for Optical Microscopy

Single image super-resolution (SISR) neural networks for optical microscopy have shown great capability to directly transform a low-resolution (LR) image into its super-resolution (SR) counterpart, enabling low-cost long-term live-cell SR imaging. However, when processing time-lapse data, current SISR models failed to exploit the important temporal dependencies between neighbor frames, often resulting in temporally inconsistent outputs. Besides, SISR models are subject to inference uncertainty that is hard to accurately quantify, therefore it is difficult to determine to what extend can we trust the inferred SR images. Here, we first build a large-scale, high-quality fluorescence microscopy dataset for the time-lapse image super-resolution (TISR) task, and conducted a comprehensive evaluation on two essential components of TISR neural networks, i.e., propagation and alignment. Second, we devised a deformable phase-space alignment (DPA) based TISR neural network (DPA-TISR), which adaptively enhances the cross-frame alignment in the phase domain and outperforms existing state-of-the-art SISR and TISR models. Third, we combined the Bayesian training scheme and Monte Carlo dropout with DPA-TISR, developing Bayesian DPA-TISR, and designed an expected calibration error (ECE)minimization framework to obtain a well-calibrated confidence map along with each output SR image, which reliably implicates potential inference errors. We demonstrate the unique characteristics of Bayesian DPA-TISR underlie the ultralong-term live-cell SR imaging capability with high spatial fidelity, superb temporal consistency, and accurate confidence quantification on a wide variety of bioprocesses.

biophysics↗

bioRxiv2024

Generators of the frequency-following response in the subthalamic nucleus: implications for non-invasive deep brain stimulation

While Deep Brain Stimulation (DBS) is effective treatment for several movement disorders, non-invasive stimulation modes have major clinical relevance. We report on a novel method holding potential for non-invasive subthalamic nucleus (STN) stimulation. We used an auditory frequency-following response task (FFR), a popular tool for studying the auditory brainstem as the neural response in the cortical and midbrain generator, as it precisely reflects the ongoing dynamics of a speech or non-speech sound. We recorded EEG and DBS electrodes from 5 patients, in 4 from the STN, and one from the anterior thalamus and a number of cortical and subcortical areas located in the hippocampus and frontal regions, during an FFR at a frequency higher than the upper limit of phase-locking in the cortex (333Hz). Our results revealed a neural response local to the STN, but not other structures. This finding is novel. Auditory perception in the basal ganglia is rather unexplored, and the STN generator of the FFR has likely gone unseen due to the limitations of our tools and research focus. The potential clinical implications are far-reaching. Future research should investigate whether auditory stimuli at common electrical stimulation frequencies and waveforms of electrical DBS stimulation can induce clinical improvement.

neuroscience↗

bioRxiv2024

An ingestible, battery-free, tissue-adhering robotic interface for non-invasive and chronic electrostimulation of the gut

Ingestible electronics have the capacity to transform our ability to effectively diagnose and potentially treat a broad set of conditions. Current applications could be significantly enhanced by addressing poor electrode-tissue contact, lack of navigation, short dwell time, and limited battery life. Here we report the development of an ingestible, battery-free, and tissue-adhering robotic interface (IngRI) for non-invasive and chronic electrostimulation of the gut, which addresses challenges associated with contact, navigation, retention, and powering (C-N-R-P) faced by existing ingestibles. We show that near-field inductive coupling operating near 13.56 MHz was sufficient to power and modulate the IngRI to deliver therapeutically relevant electrostimulation, which can be further enhanced by a bio-inspired, hydrogel-enabled adhesive interface. In swine models, we demonstrated the electrical interaction of IngRI with the gastric mucosa by recording conductive signaling from the subcutaneous space. We further observed changes in plasma ghrelin levels, the "hunger hormone," while IngRI was activated in vivo, demonstrating its clinical potential in regulating appetite and treating other endocrine conditions. The results of this study suggest that concepts inspired by soft and wireless skin-interfacing electronic devices can be applied to ingestible electronics with potential clinical applications for evaluating and treating gastrointestinal conditions.

bioengineering↗

bioRxiv2024

ExpOmics: a comprehensive web platform empowering biologists with robust multi-omics data analysis capabilities

MotivationHigh-throughput technologies have yielded a broad spectrum of multi-omics datasets, offering unparalleled insights into complex biological systems. However, effectively analyzing this diverse array of data presents challenges, given factors such as species diversity, data types, costs, and limitations of available tools. ResultsWe propose ExpOmics, a comprehensive web platform featuring seven applications and four toolkits with 28 customizable analysis functions, spanning various aspects of differential expression, co-expression, WGCNA analysis, feature selection, and functional enrichment analysis. ExpOmics empowers users to effortlessly upload and explore multi-omics data without organism restriction, supporting a wide array of data types including gene, mRNA, lncRNA, miRNA, circRNA, piRNA, and protein expression data. It is compatible with diverse gene nomenclatures and expression value types. Moreover, ExpOmics enables users to comprehensive analysis of 22,427 transcriptomic datasets sourced from 63 projects and 196 cancer subtypes in TCGA, discovering cancer biomarkers and targets. The analysis results from ExpOmics are visually presented in high-quality graphical formats suitable for publication, available for free download. In summary, ExpOmics can serves as a robust platform for global researchers to delve into diverse expression datasets, gain biological insights, and formulate testable hypotheses. Availability and implementationExpOmics is available at http://www.biomedical-web.com/expomics.

bioinformatics↗

bioRxiv2024

Harnessing defective interfering particles and lipid nanoparticles for effective delivery of an anti-dengue virus RNA therapy

Presently, no approved antiviral drug targets dengue virus (DENV) infection. Treatment mainly relies on supportive measures, while DENV vaccines efficacy varies based on factors like vaccine type, circulating DENV serotypes and vaccinated population. This study explores using defective interfering particles (DIPs) and lipid nanoparticles (LNPs) to deliver an anti-DENV defective interfering RNA, known as DI290. Results showed that both DIPs and DI290 loaded LNPs (LNP-290) effectively suppressed DENV infection in human primary monocyte-derived macrophages (MDMs), THP-1 macrophages and human fibroblasts, representing cell types naturally targeted by DENV. Furthermore, LNP-290 demonstrated >log10 inhibition of DENV viral loads in IFNAR-deficient mice, which lack functional type I interferon (IFN) receptors. DI290-mediated inhibition was also effective in IFN regulatory factor 3 and 7 double knockout mice. RNA-Seq data from LNP-treated C57BL/6J mice, IFNAR-deficient mice and human MDMs treated with LNPs or DENV DIPs illustrated DI290 treatment heightened IFN responses, particularly IFN{gamma}, as well as IFN/{beta} and IFN{lambda}. DI290 thus induces a broad range of IFN responses, with IFN{gamma} and IFN{lambda} providing anti-viral activity when IFN/{beta} responses are absent. Mice administered LNP-290 also did not manifest acute overt clinical signs. In summary, these experiments suggest DI290s potential as a therapeutic approach for combating DENV infection.

microbiology↗

bioRxiv2024

A high-continuity and annotated reference genome of allotetraploid Siberian wildrye (Elymus sibiricus L., Poaceae: Triticeae)

Elymus sibiricus L. (Siberian wildrye, Es), a species belonging to the wheat tribe, is extensively employed as forage and for the reclamation of degraded grasslands within the Qinghai-Tibet Plateau (QTP). This study provides a high-quality reference genome assembly for the allotetraploid Es, which is composed of 14 pseudomolecules with the total genome size of 6.57 Gb. Our finding suggest that large-scale bursts of retrotransposons are critical for the genome expansion of Es. We discovered a translocation event between the Es4H and Es6H chromosomes with a low frequency of combination. Phylogenetic analyses of 90 Es accessions and 25 diploid accessions representing proposed ancestors from various habitats revealed the existence of four distinct populations. We further provided support for the hypothesis that the QTP is the center of origin and genetic diversity for Es. Collectively, our study offers valuable insights into the evolution of Es, as well as providing genomic resources for genetic enhancement in the Elymus genus and wheat tribe.

genomics↗

bioRxiv2024

Metabolically intact nuclei are fluidized by the activity of the chromatin remodeling motor BRG1

The structure and dynamics of the cell nucleus regulate nearly every facet of the cell. Changes in nuclear shape limit cell motility and gene expression. Although the nucleus is generally seen as the stiffest organelle in the cell, cells can nevertheless deform the nucleus to large strains by small mechanical stresses. Here, we show that the mechanical response of the cell nucleus exhibits active fluidization that is driven by the BRG 1 motor of the SWI/SNF/BAF chromatin-remodeling complex. Atomic force microscopy measurements show that the nucleus alters stiffness in response to the cell substrate stiffness, which is retained after the nucleus is isolated and that the work of nuclear compression is mostly dissipated rather than elastically stored. Inhibiting BRG 1 stiffens the nucleus and eliminates dissipation and nuclear remodeling both in isolated nuclei and in intact cells. These findings demonstrate a novel link between nuclear motor activity and global nuclear mechanics.

cell biology↗

bioRxiv2024

Microbial Analysis and Sanitization of Hydroponic Farming Facilities in Singapore

This study performed microbial analysis of nutrient film technique (NFT) hydroponic systems at three indoor farms in Singapore. To justify the necessity to sanitize the hydroponic systems, strong biofilm-forming bacteria were isolated from the facility and investigated with their influence on Salmonella colonizing on polyvinyl chloride (PVC) coupons in hydroponic nutrient solutions. Last, sanitization solutions were evaluated with both laboratory-scale and field-scale tests. As a result, the microbiome composition in NFT systems was found to be highly farm-specific. Strong biofilm formers Corynebacterium tuberculostearicum C2 and Pseudoxanthomonas mexicana C3 were found to facilitate the attachment and colonization of Salmonella on PVC coupons. When forming dual-species biofilms, the presence of C2 and C3 also significantly promoted the growth of Salmonella (P < 0.05). Sodium hypochlorite (NaOCl) exhibited superior efficacy in biofilm removal compared to hydrogen peroxide (H2O2) and sodium percarbonate (SPC). NaOCl at 50 ppm reduced C2 and C3 counts to < 1 log CFU/cm2 within 12 h, whereas neither 3% H2O2 nor 1% SPC achieved such an effect. In operational hydroponic systems, the concentration of NaOCl needed to achieve biofilm elimination increased to 500 ppm, likely due to the presence of organic matter accumulated during the crop cultivation and the higher persistence of the naturally formed multispecies biofilms. The sanitization (500 ppm NaOCl for 12 h) did not impede subsequent plant growth but chlorination by-product chlorate was detected with high levels from the hydroponic solution and plants in the sanitized systems without rinsing. IMPORTANCEThis studys significance lies first in its elucidation of the necessity to sanitize the hydroponic farming systems. The microbiome in hydroponic systems, although most of the times non-pathogenic, might serve as a hotbed for pathogens colonization and thus pose a higher risk for food safety. We thus explored sanitization solutions with both laboratory-scale and field-scale tests. Of the three tested sanitizers, NaOCl was the most effective and economical option, whereas one must note the vital importance of rinsing the hydroponic systems after sanitization with NaOCl.

microbiology↗

bioRxiv2024

Elevated pyramidal cell firing orchestrates arteriolar vasoconstriction through COX-2-derived prostaglandin E2 signaling

Neurovascular coupling, linking neuronal activity to cerebral blood flow, is essential for brain function and underpins functional brain imaging. Whereas mechanisms involved in vasodilation are well-documented, those controlling vasoconstriction remain overlooked. This study unravels the mechanisms by which pyramidal cells elicit arteriole vasoconstriction. Using patch-clamp recording, vascular and Ca2+ imaging in mouse cortical slices, we show that strong optogenetic activation of layer II/III pyramidal cells induces vasoconstriction, correlating with firing frequency and somatic Ca2+ increase. Ex vivo and in vivo pharmacological investigations indicate that this vasoconstriction predominantly recruits prostaglandin E2 through the cyclooxygenase-2 pathway, and activation of EP1 and EP3 receptors. We also present evidence that specific interneurons releasing neuropeptide Y, and astrocytes, through 20-hydroxyeicosatetraenoic acid, contribute to this process. By revealing the mechanisms by which pyramidal cells lead to vasoconstriction, our findings shed light on the complex regulation of neurovascular coupling. Significance statementCerebral blood flow is tightly controlled by neuronal activity, a process termed neurovascular coupling which serves as the physiological basis for functional brain imaging widely used to map neuronal activity in health and diseases. While the prevailing view links increased neuronal activity with enhanced blood perfusion, our data suggest that elevated neuronal activity can also reduce cerebral blood flow. By optically controlling the activity of pyramidal cells, we demonstrate that these excitatory neurons induce vasoconstriction when their action potential firing is increased by releasing glutamate and lipid messengers. These findings update the interpretation of functional brain imaging signals and help to better understand the etiopathogenesis of epilepsy and Alzheimers disease, in which hyperactivity, hypoperfusion and cognitive deficits overlap.

neuroscience↗

bioRxiv2024

An EEG Signature of MCH Neuron Activities Predicts Cocaine Seeking

BackgroundIdentifying biomarkers that predict substance use disorder (SUD) propensity may better strategize anti-addiction treatment. The melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LH) critically mediates interactions between sleep and substance use; however, their activities are largely obscured in surface electroencephalogram (EEG) measures, hindering the development of biomarkers. MethodsSurface EEG signals and real-time Ca2+ activities of LH MCH neurons (Ca2+MCH) were simultaneously recorded in male and female adult rats. Mathematical modeling and machine learning were then applied to predict Ca2+MCH using EEG derivatives. The robustness of the predictions was tested across sex and treatment conditions. Finally, features extracted from the EEG-predicted Ca2+MCH either before or after cocaine experience were used to predict future drug-seeking behaviors. ResultsAn EEG waveform derivative - a modified theta-to-delta ratio (EEG Ratio) - accurately tracks real-time Ca2+MCH in rats. The prediction was robust during rapid eye movement sleep (REMS), persisted through REMS manipulations, wakefulness, circadian phases, and was consistent across sex. Moreover, cocaine self-administration and long-term withdrawal altered EEG Ratio suggesting shortening and circadian redistribution of synchronous MCH neuron activities. In addition, features of EEG Ratio indicative of prolonged synchronous MCH neuron activities predicted lower subsequent cocaine seeking. EEG Ratio also exhibited advantages over conventional REMS measures for the predictions. ConclusionsThe identified EEG Ratio may serve as a non-invasive measure for assessing MCH neuron activities in vivo and evaluating REMS; it may also serve as a potential biomarker predicting drug use propensity.

neuroscience↗

bioRxiv2024

Paradigm shift in biomarker translation: a pipeline to generate clinical grade biomarker candidates from DIA-MS discovery

Clinical biomarker development has been stymied by inaccurate protein quantification from mass spectrometry (MS) discovery data and a prolonged validation process. To mitigate these issues, we created the Targeted Extraction Assessment of Quantification (TEAQ) software package. This innovative tool uses the discovery cohort analysis to select precursors, peptides, and proteins that adhere to established targeted assay criteria. TEAQ was applied to Data-Independent Acquisition MS data from plasma samples acquired on an Orbitrap Astral MS. Identified precursors were evaluated for linearity, specificity, repeatability, reproducibility, and intra-protein correlation from 11-point loading curves under three throughputs, to develop a resource for clinical-grade targeted assays. From a clinical cohort of individuals with inflammatory bowel disease (n=492), TEAQ successfully identified 1116 signature peptides for 327 quantifiable proteins from 1180 identified proteins. Embedding stringent selection criteria adaptable to targeted assay development into the analysis of discovery data will streamline the transition to validation and clinical studies.

biochemistry↗

bioRxiv2024

BRD8 guards the pluripotent state by sensing and maintaining histone acetylation

Epigenetic control of cell fates is a critical determinant to maintain cell type stability and permissive differentiation. However, the epigenetic control mechanisms are not well understood. Here, we show that the histone acetyltransferase reader protein BRD8 impairs the conversion of primed mouse EpiSCs (epiblast stem cells) to naive mouse ESCs (embryonic stem cells). BRD8 works by maintaining histone acetylation on promoters and transcribed gene bodies. BRD8 is responsible for maintaining open chromatin at somatic genes, and histone acetylation at naive-specific genes. When Brd8 expression was reduced, chromatin accessibility was unchanged, but histone acetylation at primed-specific genes was reduced. Conversely, naive-specific genes had reduced repressive chromatin marks, and acquired accessible chromatin more rapidly during the cell type conversion. We show that this process requires active histone deacetylation to promote the conversion of primed to naive. Our data supports a model for BRD8 reading histone acetylation to accurately localize the genome-wide binding of the histone acetyltransferase KAT5. Overall, this study shows how the reading of the histone acetylation state by BRD8 maintains cell type stability. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/585857v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@199139forg.highwire.dtl.DTLVardef@d735c6org.highwire.dtl.DTLVardef@10b6e15org.highwire.dtl.DTLVardef@16863cf_HPS_FORMAT_FIGEXP M_FIG C_FIG Key findingsO_LIBRD8 blocks the primed-to-naive transition. C_LIO_LIReduced Brd8 promoted the suppression of somatic and primed genes through reduced chromatin repression. C_LIO_LIReduced Brd8 enabled the accelerated activation of naive-specific genes by opening chromatin. C_LIO_LIBRD8 anchors the histone acetyltransferase KAT5 to acetylated genomic loci. C_LI

cell biology↗