Proc Natl Acad Sci U S A. 2024 Nov 5;121(45):e2402277121. doi: 10.1073/pnas.2402277121. Epub 2024 Nov 1.

ABSTRACT

Carboxysomes are protein microcompartments found in cyanobacteria, whose shell encapsulates rubisco at the heart of carbon fixation in the Calvin cycle. Carboxysomes are thought to locally concentrate CO2 in the shell interior to improve rubisco efficiency through selective metabolite permeability, creating a concentrated catalytic center. However, permeability coefficients have not previously been determined for these gases, or for Calvin-cycle intermediates such as bicarbonate ([Formula: see text]), 3-phosphoglycerate, or ribulose-1,5-bisphosphate. Starting from a high-resolution cryogenic electron microscopy structure of a synthetic [Formula: see text]-carboxysome shell, we perform unbiased all-atom molecular dynamics to track metabolite permeability across the shell. The synthetic carboxysome shell structure, lacking the bacterial microcompartment trimer proteins and encapsulation peptides, is found to have similar permeability coefficients for multiple metabolites, and is not selectively permeable to [Formula: see text] relative to CO2. To resolve how these comparable permeabilities can be reconciled with the clear role of the carboxysome in the CO2-concentrating mechanism in cyanobacteria, complementary atomic-resolution Brownian Dynamics simulations estimate the mean first passage time for CO2 assimilation in a crowded model carboxysome. Despite a relatively high CO2 permeability of approximately 10-2 cm/s across the carboxysome shell, the shell proteins reflect enough CO2 back toward rubisco that 2,650 CO2 molecules can be fixed by rubisco for every 1 CO2 molecule that escapes under typical conditions. The permeabilities determined from all-atom molecular simulation are key inputs into flux modeling, and the insight gained into carbon fixation can facilitate the engineering of carboxysomes and other bacterial microcompartments for multiple applications.

PMID:39485798 | DOI:10.1073/pnas.2402277121

Elife. 2024 Nov 1;13:RP94811. doi: 10.7554/eLife.94811.

ABSTRACT

The mRNA 5'-cap structure removal by the decapping enzyme DCP2 is a critical step in gene regulation. While DCP2 is the catalytic subunit in the decapping complex, its activity is strongly enhanced by multiple factors, particularly DCP1, which is the major activator in yeast. However, the precise role of DCP1 in metazoans has yet to be fully elucidated. Moreover, in humans, the specific biological functions of the two DCP1 paralogs, DCP1a and DCP1b, remain largely unknown. To investigate the role of human DCP1, we generated cell lines that were deficient in DCP1a, DCP1b, or both to evaluate the importance of DCP1 in the decapping machinery. Our results highlight the importance of human DCP1 in decapping process and show that the EVH1 domain of DCP1 enhances the mRNA-binding affinity of DCP2. Transcriptome and metabolome analyses outline the distinct functions of DCP1a and DCP1b in human cells, regulating specific endogenous mRNA targets and biological processes. Overall, our findings provide insights into the molecular mechanism of human DCP1 in mRNA decapping and shed light on the distinct functions of its paralogs.

PMID:39485278 | DOI:10.7554/eLife.94811

Cancer Discov. 2024 Nov 1;14(11):2061-2065. doi: 10.1158/2159-8290.CD-24-0836.

ABSTRACT

Significant efforts have been made to identify and validate oncoproteins and ncRNAs as therapeutic targets for cancer therapy; however, emerging observations suggest that noncoding cis-regulatory elements, which orchestrate the 3D organization of the genome and thus the transcriptional landscape, are potential therapeutic targets as well. In this commentary, we envisage that further efforts to decipher the noncoding cis-regulatory code and performing systematic surveys of functional noncoding cis-regulatory elements and recurrent 3D genome alterations in both cancerous and nonmalignant cells within tumor tissues will pave the way to the development of novel therapeutic strategies.

PMID:39485254 | DOI:10.1158/2159-8290.CD-24-0836

Cancer Discov. 2024 Nov 1;14(11):2041-2046. doi: 10.1158/2159-8290.CD-24-0833.

ABSTRACT

Despite an increasingly detailed understanding of cancer hallmarks at molecular or atomic resolution, most studies, however, fall short of investigating the systemic interactions of cancer with the human body. We propose to investigate the hallmarks of cancer from an organ-wide macroscopic view, discuss the challenges in preclinical and clinical research to study the cross-organ regulation of cancer together with potential directions to overcome these challenges, and foresee how this holistic view may be translated into more effective therapies.

PMID:39485247 | DOI:10.1158/2159-8290.CD-24-0833

bioRxiv [Preprint]. 2024 Oct 24:2024.10.24.619934. doi: 10.1101/2024.10.24.619934.

ABSTRACT

Morphology is a cardinal feature of a neuron that mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide study of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstructed and reference-atlas mapped striatal D1- and D2- medium spiny neurons (MSNs). Integrative morphometric analyses reveal distinct impacts of anatomical locations and D1/D2 genetic types on MSN morphologies. To analyze striatal regional features of MSN dendrites without prior anatomical constraints, we assigned MSNs to a lattice of cubic boxes in the reference brain atlas, and summarized morphometric representation ("eigen-morph") for each box and clustered boxes with shared morphometry. This analysis reveals 6 modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found aging confers robust dendritic length and branching defects in MSNs, while Huntington's disease (HD) mice exhibit selective length-related defects. Together, our study demonstrates a systems-biology approach to profile dendritic morphology of genetically-defined single-neurons; and defines novel striatal D1/D2-MSN morphological territories and aging- or HD-associated pathologies.

PMID:39484488 | PMC:PMC11526962 | DOI:10.1101/2024.10.24.619934

bioRxiv [Preprint]. 2024 Oct 21:2024.10.17.618956. doi: 10.1101/2024.10.17.618956.

ABSTRACT

Our understanding of age-related physiology and metabolism has grown through the study of systems biology, including transcriptomics, single-cell analysis, proteomics and metabolomics. Studies in lab organisms in controlled environments, while powerful and complex, fall short of capturing the breadth of genetic and environmental variation in nature. Thus, there is now a major effort in geroscience to identify aging biomarkers and to develop aging interventions that might be applied across the diversity of humans and other free-living species. To meet this challenge, the Dog Aging Project (DAP) is designed to identify cross-sectional and longitudinal patterns of aging in complex systems, and how these are shaped by the diversity of genetic and environmental variation among companion dogs. Here we surveyed the plasma metabolome from the first year of sampling of the Precision Cohort of the DAP. By incorporating extensive metadata and whole genome sequencing information, we were able to overcome the limitations inherent in breed-based estimates of genetic and physiological effects, and to probe the physiological and dietary basis of the age-related metabolome. We identified a significant effect of age on approximately 40% of measured metabolites. Among other insights, we discovered a potentially novel biomarker of age in the post-translationally modified amino acids (ptmAAs). The ptmAAs, which can only be generated by protein hydrolysis, covaried both with age and with other biomarkers of amino acid metabolism, and in a way that was robust to diet. Clinical measures of kidney function mediated about half of the higher ptmAA levels in older dogs. This work identifies ptmAAs as robust indicators of age in dogs, and points to kidney function as a physiological mediator of age-associated variation in the plasma metabolome.

PMID:39484426 | PMC:PMC11526923 | DOI:10.1101/2024.10.17.618956

bioRxiv [Preprint]. 2024 Oct 25:2024.10.25.619450. doi: 10.1101/2024.10.25.619450.

ABSTRACT

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) accounts for ∼50% of HF cases, with no effective treatments. The ZSF1-obese rat model recapitulates numerous clinical features of HFpEF including hypertension, obesity, metabolic syndrome, exercise intolerance, and LV diastolic dysfunction. Here, we utilized a systems-biology approach to define the early metabolic and transcriptional signatures to gain mechanistic insight into the pathways contributing to HFpEF development.

METHODS: Male ZSF1-obese, ZSF1-lean hypertensive controls, and WKY (wild-type) controls were compared at 14w of age for extensive physiological phenotyping and LV tissue harvesting for unbiased metabolomics, RNA-sequencing, and assessment of mitochondrial morphology and function. Utilizing ZSF1-lean and WKY controls enabled a distinction between hypertension-driven molecular changes contributing to HFpEF pathology, versus hypertension + metabolic syndrome.

RESULTS: ZSF1-obese rats displayed numerous clinical features of HFpEF. Comparison of ZSF1-lean vs WKY (i.e., hypertension-exclusive effects) revealed metabolic remodeling suggestive of increased aerobic glycolysis, decreased β-oxidation, and dysregulated purine and pyrimidine metabolism with few transcriptional changes. ZSF1-obese rats displayed worsened metabolic remodeling and robust transcriptional remodeling highlighted by the upregulation of inflammatory genes and downregulation of the mitochondrial structure/function and cellular metabolic processes. Integrated network analysis of metabolomic and RNAseq datasets revealed downregulation of nearly all catabolic pathways contributing to energy production, manifesting in a marked decrease in the energetic state (i.e., reduced ATP/ADP, PCr/ATP). Cardiomyocyte ultrastructure analysis revealed decreased mitochondrial area, size, and cristae density, as well as increased lipid droplet content in HFpEF hearts. Mitochondrial function was also impaired as demonstrated by decreased substrate-mediated respiration and dysregulated calcium handling.

CONCLUSIONS: Collectively, the integrated omics approach applied here provides a framework to uncover novel genes, metabolites, and pathways underlying HFpEF, with an emphasis on mitochondrial energy metabolism as a potential target for intervention.

PMID:39484400 | PMC:PMC11527111 | DOI:10.1101/2024.10.25.619450

Front Public Health. 2024 Oct 17;12:1480805. doi: 10.3389/fpubh.2024.1480805. eCollection 2024.

ABSTRACT

BACKGROUND: Corona Virus Disease 2019 (COVID-19) has severely impacted global health, resulting in high morbidity and mortality, and overwhelming healthcare systems, particularly in Iran. Understanding reinfection is crucial as it has significant implications for immunity, public health strategies, and vaccine development. This study aims to identify rate and the risk factors associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) reinfection and compare the clinical course of initial infection versus reinfection in readmitted COVID-19 patients in Iran.

METHODS: This retrospective cohort study was conducted from January 2020 to the end of 2022 in five hospitals in Iran. The study compared demographic and clinical data, vaccination status, and clinical outcomes between patients with reinfection (defined as a positive PCR test for SARS-CoV-2 at least 90 days after the primary admission) and a control group (patients who had an initial confirmed SARS-CoV-2 infection but were not readmitted with a positive PCR test for SARS-CoV-2 at least 90 days after their primary infection). Risk factors for reinfection were evaluated using a regression model. Propensity score matching (PSM) was used to compare post-clinical and laboratory outcomes between the matched case and control groups.

RESULTS: Out of 31,245 patients, 153 (0.49%) experienced reinfections. The reinfection rate was significantly higher during B.1.617.2 and B.1.1.529 variant wave (p < 0.001). After multivariable regression analysis, incomplete vaccination status (OR: 1.68, 95% CI: 1.34-2.31, p = 0.021) and lack of booster vaccination (OR: 2.48, 95% CI: 1.96-3.65, p = 0.001) were the risk factors for reinfection. Furthermore, reinfection was associated with atypical COVID-19 symptoms, and shorter ICU and hospital stays (p < 0.001). The B.1.1.529 variant was significantly more common among reinfected patients (p < 0.001).

CONCLUSION: SARS-CoV-2 reinfections are more frequently observed during waves of novel variants and are associated with a milder clinical course and shorter hospital stays. Full vaccination and booster doses can effectively reduce the risk of SARS-CoV-2 reinfections.

PMID:39484354 | PMC:PMC11524883 | DOI:10.3389/fpubh.2024.1480805

PeerJ. 2024 Oct 28;12:e18421. doi: 10.7717/peerj.18421. eCollection 2024.

ABSTRACT

Innate immunity in asthma may be influenced by alterations in lung microbiota, potentially affecting disease severity. This study investigates the differences in lung inflammation and microbiome between asthma-ovalbumin (OVA) administered with and without fluconazole treatment in C57BL/6 mice. Additionally, the role of inflammation was examined in an in vitro study using a pulmonary cell line. At 30 days post-OVA administration, allergic asthma mice exhibited increased levels of IgE and IL-4 in serum and lung tissue, higher pathological scores, and elevated eosinophils in bronchoalveolar lavage fluid (BALF) compared to control mice. Asthma inflammation was characterized by elevated serum IL-6, increased lung cytokines (TNF-α, IL-6, IL-10), and higher fungal abundance confirmed by polymerase chain reaction (PCR). Fluconazole-treated asthma mice displayed higher levels of cytokines in serum and lung tissue (TNF-α and IL-6), increased pathological scores, and a higher number of mononuclear cells in BALF, with undetectable fungal levels compared to untreated mice. Lung microbiome analysis revealed similarities between control and asthma mice; however, fluconazole-treated asthma mice exhibited higher Bacteroidota levels, lower Firmicutes, and reduced bacterial abundance. Pro-inflammatory cytokine production was increased in supernatants of the pulmonary cell line (NCI-H292) after co-stimulation with LPS and beta-glucan (BG) compared to LPS alone. Fluconazole treatment in OVA-induced asthma mice exacerbated inflammation, partially due to fungi and Gram-negative bacteria, as demonstrated by LPS+BG-activated pulmonary cells. Therefore, fluconazole should be reserved for treating fungal asthma rather than asthma caused by other etiologies.

PMID:39484217 | PMC:PMC11526796 | DOI:10.7717/peerj.18421

Front Plant Sci. 2024 Oct 17;15:1361183. doi: 10.3389/fpls.2024.1361183. eCollection 2024.

ABSTRACT

Plant growth and development are characterized by systematic and continuous processes, each involving intricate metabolic coordination mechanisms. Mathematical models are essential tools for investigating plant growth and development, metabolic regulation networks, and growth patterns across different stages. These models offer insights into secondary metabolism patterns in plants and the roles of metabolites. The proliferation of data related to plant genomics, transcriptomics, proteomics, and metabolomics in the last decade has underscored the growing importance of mathematical modeling in this field. This review aims to elucidate the principles and types of metabolic models employed in studying plant secondary metabolism, their strengths, and limitations. Furthermore, the application of mathematical models in various plant systems biology subfields will be discussed. Lastly, the review will outline how mathematical models can be harnessed to address research questions in this context.

PMID:39483677 | PMC:PMC11524811 | DOI:10.3389/fpls.2024.1361183

Biol Sex Differ. 2024 Oct 31;15(1):89. doi: 10.1186/s13293-024-00666-4.

ABSTRACT

BACKGROUND: Aging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues.

METHODS: We collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type.

RESULTS: We identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction.

CONCLUSIONS: There are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

PMID:39482778 | DOI:10.1186/s13293-024-00666-4

Genome Biol. 2024 Oct 31;25(1):284. doi: 10.1186/s13059-024-03424-2.

ABSTRACT

BACKGROUND: Transcription factors (TFs) bind to DNA in a highly sequence-specific manner. This specificity manifests itself in vivo as differences in TF occupancy between the two alleles at heterozygous loci. Genome-scale assays such as ChIP-seq currently are limited in their power to detect allele-specific binding (ASB) both in terms of read coverage and representation of individual variants in the cell lines used. This makes prediction of allelic differences in TF binding from sequence alone desirable, provided that the reliability of such predictions can be quantitatively assessed.

RESULTS: We here propose methods for benchmarking sequence-to-affinity models for TF binding in terms of their ability to predict allelic imbalances in ChIP-seq counts. We use a likelihood function based on an over-dispersed binomial distribution to aggregate evidence for allelic preference across the genome without requiring statistical significance for individual variants. This allows us to systematically compare predictive performance when multiple binding models for the same TF are available. To facilitate the de novo inference of high-quality models from paired-end in vivo binding data such as ChIP-seq, ChIP-exo, and CUT&Tag without read mapping or peak calling, we introduce an extensible reimplementation of our biophysically interpretable machine learning framework named PyProBound. Explicitly accounting for assay-specific bias in DNA fragmentation rate when training on ChIP-seq yields improved TF binding models. Moreover, we show how PyProBound can leverage our threshold-free ASB likelihood function to perform de novo motif discovery using allele-specific ChIP-seq counts.

CONCLUSION: Our work provides new strategies for predicting the functional impact of non-coding variants.

PMID:39482734 | DOI:10.1186/s13059-024-03424-2

Nat Methods. 2024 Oct 31. doi: 10.1038/s41592-024-02471-8. Online ahead of print.

ABSTRACT

Across biological systems, cells undergo coordinated changes in gene expression, resulting in transcriptome dynamics that unfold within a low-dimensional manifold. While low-dimensional dynamics can be extracted using RNA velocity, these algorithms can be fragile and rely on heuristics lacking statistical control. Moreover, the estimated vector field is not dynamically consistent with the traversed gene expression manifold. To address these challenges, we introduce a Bayesian model of RNA velocity that couples velocity field and manifold estimation in a reformulated, unified framework, identifying the parameters of an explicit dynamical system. Focusing on the cell cycle, we implement VeloCycle to study gene regulation dynamics on one-dimensional periodic manifolds and validate its ability to infer cell cycle periods using live imaging. We also apply VeloCycle to reveal speed differences in regionally defined progenitors and Perturb-seq gene knockdowns. Overall, VeloCycle expands the single-cell RNA sequencing analysis toolkit with a modular and statistically consistent RNA velocity inference framework.

PMID:39482463 | DOI:10.1038/s41592-024-02471-8

Sci Rep. 2024 Nov 1;14(1):26251. doi: 10.1038/s41598-024-77580-7.

ABSTRACT

Eimeria tenella is among the protozoan parasites that cause the infectious disease coccidiosis in chickens, incurring huge economic losses to the global poultry industry. Surface antigens (EtSAGs) involved in host-parasite interaction are potential targets for control strategies. However, the occurrence of genetic diversity for EtSAGs in field populations is unknown, as is the risk of such diversity to the efficacy of EtSAG-based control approaches. Here, the extent of EtSAG genetic diversity and its implications on protein structure and function is assessed. Eighty-seven full-length EtSAG genomic sequences were identified from E. tenella genome assemblies of isolates sampled from continents including North America (United States), Europe (United Kingdom), Asia (Malaysia and Japan) and Africa (Nigeria). Limited diversity was observed in the EtSAG sequences. However, distinctive patterns of polymorphism were identified between EtSAG subfamilies, suggesting functional differences among these antigen families. Polymorphisms were sparsely distributed across isolates, with a small number of variants exclusive to specific geographical regions. These findings enhance our understanding of EtSAGs, particularly in elucidating functional differences among the antigens that could inform the development of more effective and long-lasting anticoccidial control strategies.

PMID:39482455 | DOI:10.1038/s41598-024-77580-7

Mov Disord. 2024 Oct 31. doi: 10.1002/mds.30051. Online ahead of print.

NO ABSTRACT

PMID:39482233 | DOI:10.1002/mds.30051

Methods. 2024 Oct 29:S1046-2023(24)00236-6. doi: 10.1016/j.ymeth.2024.10.011. Online ahead of print.

ABSTRACT

Rapid and accurate identification of bacterial pathogens is crucial for effective treatment and infection control, particularly in hospital settings. Conventional methods like culture techniques and MALDI-TOF mass spectrometry are often time-consuming and less sensitive. This study addresses the need for faster and more precise diagnostic methods by developing novel digital PCR (dPCR) assays for the rapid quantification of biomarkers from three Gram-negative bacteria: Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Utilizing publicly available genomes and the rapid identification of PCR primers for unique core sequences or RUCS algorithm, we designed highly specific dPCR assays. These assays were validated using synthetic DNA, bacterial genomic DNA, and DNA extracted from clinical samples. The developed dPCR methods demonstrated wide linearity, a low limit of detection (∼30 copies per reaction), and robust analytical performance with measurement uncertainty below 25 %. The assays showed high repeatability and intermediate precision, with no cross-reactivity observed. Comparison with MALDI-TOF mass spectrometry revealed substantial concordance, highlighting the methods' suitability for clinical diagnostics. This study underscores the potential of dPCR for rapid and precise quantification of Gram-negative bacterial biomarkers. The developed methods offer significant improvements over existing techniques, providing faster, more accurate, and SI-traceable measurements. These advancements could enhance clinical diagnostics and infection control practices.

PMID:39481819 | DOI:10.1016/j.ymeth.2024.10.011

J Mol Biol. 2024 Oct 29:168846. doi: 10.1016/j.jmb.2024.168846. Online ahead of print.

ABSTRACT

Global modifier genes influence the mapping of genotypes onto phenotypes and fitness through their epistatic interactions with genetic variants on a massive scale. The first such factor to be identified, Hsp90, is a highly conserved molecular chaperone that plays a central role in protein homeostasis. Hsp90 is a "hub of hubs" that chaperones proteins engaged in many key cellular and developmental regulatory networks. These clients, which are enriched in kinases, transcription factors, and E3 ubiquitin ligases, drive diverse cellular functions and are themselves highly connected. By contrast to many other hub proteins, the abundance and activity of Hsp90 changes substantially in response to shifting environmental conditions. As a result, Hsp90 modifies the functional impact of many genetic variants simultaneously in a manner that depends on environmental stress. Studies in diverse organisms suggest that this coupling between Hsp90 function and challenging environments exerts a substantial impact on what parts of the genome are visible to natural selection, expanding adaptive opportunities when most needed. In this Perspective, we explore the multifaceted role of Hsp90 as global modifier of the genotype-phenotype-fitness map as well as its implications for evolution in nature and the clinic.

PMID:39481633 | DOI:10.1016/j.jmb.2024.168846

Cell. 2024 Oct 25:S0092-8674(24)01154-1. doi: 10.1016/j.cell.2024.10.006. Online ahead of print.

ABSTRACT

Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.

PMID:39481380 | DOI:10.1016/j.cell.2024.10.006

Dev Cell. 2024 Oct 29:S1534-5807(24)00603-8. doi: 10.1016/j.devcel.2024.10.004. Online ahead of print.

ABSTRACT

Transcription factors (TFs) bind combinatorially to cis-regulatory elements, orchestrating transcriptional programs. Although studies of chromatin state and chromosomal interactions have demonstrated dynamic neurodevelopmental cis-regulatory landscapes, parallel understanding of TF interactions lags. To elucidate combinatorial TF binding driving mouse basal ganglia development, we integrated chromatin immunoprecipitation sequencing (ChIP-seq) for twelve TFs, H3K4me3-associated enhancer-promoter interactions, chromatin and gene expression data, and functional enhancer assays. We identified sets of putative regulatory elements with shared TF binding (TF-pRE modules) that orchestrate distinct processes of GABAergic neurogenesis and suppress other cell fates. The majority of pREs were bound by one or two TFs; however, a small proportion were extensively bound. These sequences had exceptional evolutionary conservation and motif density, complex chromosomal interactions, and activity as in vivo enhancers. Our results provide insights into the combinatorial TF-pRE interactions that activate and repress expression programs during telencephalon neurogenesis and demonstrate the value of TF binding toward modeling developmental transcriptional wiring.

PMID:39481376 | DOI:10.1016/j.devcel.2024.10.004

Science. 2024 Nov;386(6721):eadp7710. doi: 10.1126/science.adp7710. Epub 2024 Nov 1.

ABSTRACT

Parrots produce stunning plumage colors through unique pigments called psittacofulvins. However, the mechanism underlying their ability to generate a spectrum of vibrant yellows, reds, and greens remains enigmatic. We uncover a unifying chemical basis for a wide range of parrot plumage colors, which result from the selective deposition of red aldehyde- and yellow carboxyl-containing psittacofulvin molecules in developing feathers. Through genetic mapping, biochemical assays, and single-cell genomics, we identified a critical player in this process, the aldehyde dehydrogenase ALDH3A2, which oxidizes aldehyde psittacofulvins into carboxyl forms in late-differentiating keratinocytes during feather development. The simplicity of the underlying molecular mechanism, in which a single enzyme influences the balance of red and yellow pigments, offers an explanation for the exceptional evolutionary lability of parrot coloration.

PMID:39480920 | DOI:10.1126/science.adp7710