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Integrative analyses of transcriptomic and neuroimaging data have generated a wealth of information about biological pathways underlying regional variability in imaging-derived brain phenotypes in humans, but rarely in nonhuman primates due to the lack of a comprehensive anatomically-defined atlas of brain transcriptomics. Here we generate complementary bulk RNA-sequencing dataset of 819 samples from 110 brain regions and single-nucleus RNA-sequencing dataset, and neuroimaging data from 162 cynomolgus macaques, to examine the link between brain-wide gene expression and regional variation in morphometry. We not only observe global/regional expression profiles of macaque brain comparable to human but unravel a dorsolateral-ventromedial gradient of gene assemblies within the primate frontal lobe. Furthermore, we identify a set of 971 protein-coding and 34 non-coding genes consistently associated with cortical thickness, specially enriched for neurons and oligodendrocytes. These data provide a unique resource to investigate nonhuman primate models of human diseases and probe cross-species evolutionary mechanisms. A comprehensive anatomically-defined atlas of brain transcriptomics in macaques is still lacking. Here, the authors generate complementary bulk RNA-seq and snRNA-seq datasets from cynomolgus macaques to examine the link between brain-wide gene expression and regional variation in morphometry.

The primate cerebral cortex, the major organ for cognition, consists of an immense number of neurons. However, the organizational principles governing these neurons remain unclear. By accessing the single‐cell spatial transcriptome of over 25 million neuron cells across the entire macaque cortex, it is discovered that the distribution of neurons within cortical layers is highly non‐random. Strikingly, over three‐quarters of these neurons are located in distinct neuronal clusters. Within these clusters, different cell types tend to collaborate rather than function independently. Typically, excitatory neuron clusters mainly consist of excitatory‐excitatory combinations, while inhibitory clusters primarily contain excitatory‐inhibitory combinations. Both cluster types have roughly equal numbers of neurons in each layer. Importantly, most excitatory and inhibitory neuron clusters form spatial partnerships, indicating a balanced local neuronal network and correlating with specific functional regions. These organizational principles are conserved across mouse cortical regions. These findings suggest that different brain regions of the cortex may exhibit similar mechanisms at the neuronal population level. This study reveals that neurons in the primate cerebral cortex organize into distinct, non‐random clusters within each cortical layer. Excitatory and inhibitory neurons collaborate in balanced networks, a pattern conserved in mice. These clustered arrangements are linked to specific brain functions, uncovering fundamental principles of brain organization at the single‐cell level.

Circadian clocks temporally orchestrate the behavioural and physiological rhythms. The core molecules establishing the circadian clock are clear; however, the critical signalling pathways that cause or favour the homeostasis are poorly understood. Here, we report that anti-Müllerian hormone (Amh)-mediated signalling plays an important role in sustaining circadian homeostasis in zebrafish. Notably, amh knockout dampens molecular clock oscillations and disrupts both behavioural and hormonal circadian rhythms, which are recapitulated in bmpr2a null mutants. Somatotropes and gonadotropes are identified as Amh-targeted pituitary cell populations. Single-cell transcriptome analysis further reveals a lineage-specific regulation of pituitary clock by Amh. Moreover, Amh-induced effect on clock gene expression can be abolished by blocking Smad1/5/9 phosphorylation and bmpr2a knockout. Mechanistically, Amh binds to its receptors, Bmpr2a/Bmpr1bb, which in turn activate Smad1/5/9 by phosphorylation and promote circadian gene expression. Our findings reveal a key hormone signalling pathway for circadian homeostasis in zebrafish with implications for rhythmic organ functions and circadian health. The mechanisms underlying circadian homeostasis remain elusive. Here, the authors show that anti-Müllerian hormone (Amh)-mediated signaling sustains molecular clock oscillations in the pituitary gland, thereby maintaining circadian homeostasis at both tissue and systemic levels.

Background Circadian rhythm, regulated by both internal and external environment of the body, is a multi-scale biological oscillator of great complexity. On the molecular level, thousands of genes exhibit rhythmic transcription, which is both organ- and species-specific, but it remains a mystery whether some common factors could potentially explain their rhythmicity in different organs. In this study we address this question by analyzing the transcriptome data in 12 mouse organs to determine such major impacting factors. Results We found a strong positive correlation between the transcriptional level and rhythmic amplitude of circadian rhythmic genes in mouse organs. Further, transcriptional level could explain over 70% of the variation in amplitude. In addition, the functionality and tissue specificity were not strong predictors of amplitude, and the expression level of rhythmic genes was linked to the energy consumption associated with transcription. Conclusion Expression level is a single major factor impacts the behavior of rhythmic genes in mouse organs. This single determinant implicates the importance of rhythmic expression itself on the design of the transcriptional system. So, rhythmic regulation of highly expressed genes can effectively reduce the energetic cost of transcription, facilitating the long-term adaptive evolution of the entire genetic system.

The 5-year survival rate of non-small cell lung cancer (NSCLC) patients is very low. MicroRNAs (miRNAs) are involved in the occurrence of NSCLC. miR-122-5p interacts with wild-type p53 (wtp53), and wtp53 affects tumor growth by inhibiting the mevalonate (MVA) pathway. Therefore, this study aimed to evaluate the role of these factors in NSCLC. The role of miR-122-5p and p53 was established in samples from NSCLC patients, and human NSCLC cells A549 using the miR-122-5p inhibitor, miR-122-5p mimic, and si-p53. Our results showed that inhibiting miR-122-5p expression led to the activation of p53. This inhibited the progression of the MVA pathway in the NSCLC cells A549, hindered cell proliferation and migration, and promoted apoptosis. miR-122-5p was negatively correlated with p53 expression in p53 wild-type NSCLC patients. The expression of key genes in the MVA pathway in tumors of p53 wild-type NSCLC patients was not always higher than the corresponding normal tissues. The malignancy of NSCLC was positively correlated with the high expression of the key genes in the MVA pathway. Therefore, miR-122-5p regulated NSCLC by targeting p53, providing potential molecular targets for developing targeted drugs.

Circadian oscillations are generated via transcriptional-translational negative feedback loops. However, individual cells from fibroblast cell lines have heterogeneous rhythms, oscillating independently and with different period lengths. Here we showed that heterogeneity in circadian period is heritable and used a multi-omics approach to investigate underlying mechanisms. By examining large-scale phenotype-associated gene expression profiles in hundreds of mouse clonal cell lines, we identified and validated multiple novel candidate genes involved in circadian period determination in the absence of significant genomic variants. We also discovered differentially co-expressed gene networks that were functionally associated with period length. We further demonstrated that global differential DNA methylation bidirectionally regulated these same gene networks. Interestingly, we found that depletion of DNMT1 and DNMT3A had opposite effects on circadian period, suggesting non-redundant roles in circadian gene regulation. Together, our findings identify novel gene candidates involved in periodicity, and reveal DNA methylation as an important regulator of circadian periodicity.

Mammalian organs are individually controlled by autonomous circadian clocks. At the molecular level, this process is defined by the cyclical co-expression of both core transcription factors and their downstream targets across time. While interactions between these molecular clocks are necessary for proper homeostasis, these features remain undefined. Here, we utilize integrative analysis of a baboon diurnal transcriptome atlas to characterize the properties of gene networks under circadian control. We found that 53.4% (8120) of baboon genes are oscillating body-wide. Additionally, two basic network modes were observed at the systems level: daytime and nighttime mode. Daytime networks were enriched for genes involved in metabolism, while nighttime networks were enriched for genes associated with growth and cellular signaling. A substantial number of diseases only form significant disease modules at either daytime or nighttime. In addition, a majority of SARS-CoV-2-related genes and modules are rhythmically expressed, which have significant network proximities with circadian regulators. Our data suggest that synchronization amongst circadian gene networks is necessary for proper homeostatic functions and circadian regulators have close interactions with SARS-CoV-2 infection. Integrative analysis of the high-resolution baboon diurnal transcriptome, provides insights into the effect of circadian rhythm on the whole-body primate gene network.

Tissue specificity is a fundamental property of an organ that affects numerous biological processes, including aging and longevity, and is regulated by the circadian clock. However, the distinction between circadian-affected tissue specificity and other tissue specificities remains poorly understood. Here, using multi-omics data on circadian rhythms in mice, we discovered that approximately 35% of tissue-specific genes are directly affected by circadian regulation. These circadian-affected tissue-specific genes have higher expression levels and are associated with metabolism in hepatocytes. They also exhibit specific features in long-reads sequencing data. Notably, these genes are associated with aging and longevity at both the gene level and at the network module level. The expression of these genes oscillates in response to caloric restricted feeding regimens, which have been demonstrated to promote longevity. In addition, aging and longevity genes are disrupted in various circadian disorders. Our study indicates that the modulation of circadian-affected tissue specificity is essential for understanding the circadian mechanisms that regulate aging and longevity at the genomic level. A multi-omics study on circadian rhythms in mice suggests that ~35% of tissue-specific genes may be influenced by circadian regulation, and these genes are linked to aging and longevity.

The advanced evolution of the human cerebral cortex forms the basis for our high-level cognitive functions. Through a comparative analysis of single-nucleus transcriptome data from the human neocortex and that of chimpanzees, macaques, and marmosets, we discovered 20 subgroups of cell types unique to the human brain, which include 11 types of excitatory neurons. Many of these human-unique cell clusters exhibit significant overexpression of genes regulated by human-specific enhancers. Notably, these specific cell clusters also express genes associated with disease risk, particularly those related to brain dysfunctions like learning disorders. Furthermore, genes linked to cortical thickness and human episodic memory encoding activities show heightened expression within these cell subgroups. These findings underscore the critical role of human brain-unique cell clusters in the evolution of human brain functions.

Understanding the temporal and spatial expression patterns of the human cerebral cortex is essential for expanding knowledge of its functionality. Previous analysis focused on the differentially expressed genes (DEGs) among cortical subregions revealed an hourglass model for interareal differences. However, the overall pattern of transcriptional differences during the development of every region remains to be fully explored. Here, analysing more than 800 neocortex samples from lifespan transcriptional profiles revealed that excitatory neurons are more regulated than inhibitory neurons in the foetal brain. Developmental DEGs tend to be resting state or memory encoding-related and are also involved in autism and Alzheimer’s disease. In addition, twin peaks of DEGs occur during the development of each neocortex region, with a first peak appearing in the perinatal period and an unexpected second peak appearing around childhood. Genes in these peaks have similar functions, but the second peak is more inhibitory neuron related. All these results emphasize the significance of this unique temporal regulatory pattern for human neocortical development.