Primary cilia are hair-like structures that protrude from the cell surface. They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities. Mutations in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations, collectively known as ciliopathies. A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 diabetes. Nevertheless, the mechanisms through which dysfunction of primary cilia contributes to obesity are complex. In this article, we present an overview of primary cilia and highlight obesity-related ciliopathies. We also discuss the potential role of primary cilia in peripheral organs, with a focus on adipose tissues. In addition, we emphasize the significance of primary cilia in the central regulation of obesity, especially the involvement of ciliary signaling in the hypothalamic control of feeding behavior. This article therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia, which may benefit further exploration of the ciliary role in metabolic regulation.

Citrus sinensis is the most cultivated and economically valuable Citrus species in the world, whose genome has been assembled by three generation sequencing. However, chromosome recognition remains a problem due to the small size of chromosomes, and difficulty in differentiating between pseudo and real chromosomes because of a highly heterozygous genome. We employed fluorescence in situ hybridization (FISH) with nine chromosome painting probes, thirty oligo pools and eight repetitive sequences to visualize 18 chromosomes. Then we developed an approach to identify each chromosome in one cell through single experiment of oligo-FISH and Chromoycin A3 (CMA) staining. By this approach, we constructed a high-resolution molecular cytogenetic map containing the physical positions of CMA banding and 38 sequences of FISH including centromere regions, which enable us to visualize significant differences between homologous chromosomes. Based on the map, we located several highly repetitive sequences on chromosomes, and estimated sizes and copy numbers of each site. In particular, we discovered the translocation regions of chromosomes 4 and 9 in C. sinensis 'Valencia'. The high-resolution molecular cytogenetic map will help improve understanding of sweet orange genome assembly and also provide a fundamental reference for investigating chromosome evolution and chromosome engineering for genetic improvement in Citrus.

Screening biomolecular markers from high-dimensional biological data are one of the long-standing tasks for biomedical translational research. With its advantages in both feature shrinkage and biological interpretability, Least Absolute Shrinkage and Selection Operator (LASSO) algorithm is one of the most popular methods for the scenarios of clinical biomarker development. However, in practice, applying LASSO on omics-based data with high dimensions and low-sample size may usually result in an excess number of predictive variables, leading to the overfitting of the model. Here, we present VSOLassoBag, a wrapped LASSO approach by integrating an ensemble learning strategy to help select efficient, stable, and highly confidential variables from omics-based data. Using a bagging strategy in combination with a parametric method or inflection point search method, VSOLassoBag can integrate and vote variables generated from multiple LASSO models to determine the optimal candidates. The application of VSOLassoBag on both simulation datasets and real-world datasets shows that the algorithm can effectively identify markers for either case-control binary classification or prognosis prediction. In addition, by comparing with multiple existing algorithms, the VSOLassoBag shows a comparable performance under different scenarios while resulting in fewer features than others. In summary, VSOLassoBag, which is available at https://seqworld.com/VSOLassoBag/ under the GPL v3 license, provides an alternative strategy for selecting reliable biomarkers from high-dimensional omics data. For user's convenience, we implement VSOLassoBag as an R package that provides multithreading computing configurations.

The differentiation imbalance in bone marrow mesenchymal stem cells (BMMSCs) is critical for the development of bone density diseases as the population ages. BMMSCs are precursor cells for osteoblasts and adipocytes; however, the chromatin organization landscapes during BMMSC differentiation remain elusive. In this study, we systematically delineate the four-dimensional (4D) genome and dynamic epigenetic atlas of BMMSCs by RNA sequencing (RNA-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and high-throughput chromosome conformation capture (Hi-C). The structure analyses reveal 17.5% common and 28.5%∼30% specific loops among BMMSCs, osteoblasts, and adipocytes. The subsequent correlation of genome-wide association studies (GWAS) and expression quantitative trait locus (eQTL) data with multi-omics analysis reveal 274 genes and 3634 single nucleotide polymorphisms (SNPs) associated with bone degeneration and osteoporosis (OP). We hypothesize that SNP mutations affect transcription factor (TF) binding sites, thereby affecting changes in gene expression. Furthermore, 26 motifs, 260 TFs, and 291 SNPs are identified to affect the eQTL. Among these genes, DAAM2, TIMP2, and TMEM241 were found to be essential for diseases such as bone degeneration and OP and may serve as potential drug targets.

Gliomas are the most prevalent and aggressive malignancies of the nervous system. Previous bioinformatic studies have revealed the crucial role of the secretory pathway kinase FAM20C in the prediction of glioma invasion and malignancy. However, little is known about the pathogenesis of FAM20C in the regulation of glioma. Here, we construct the full-length transcriptome atlas in paired gliomas and observe that 22 genes are upregulated by full-length transcriptome and differential APA analysis. Analysis of ATAC-seq data reveals that both FAM20C and NPTN are the hub genes with chromatin openness and differential expression. Further in vitro and in vivo studies suggest that FAM20C stimulates the proliferation and metastasis of glioma cells. Meanwhile, NPTN, a novel cancer suppressor gene, counteracts the function of FAM20C by inhibiting both the proliferation and migration of glioma. The blockade of FAM20C by neutralizing antibodies results in the regression of xenograft tumors. Moreover, MAX, BRD4, MYC, and REST are found to be the potential trans-active factors for the regulation of FAM20C. Taken together, our results uncover the oncogenic role of FAM20C in glioma and shed new light on the treatment of glioma by abolishing FAM20C.

Transcription factors (TFs) regulate cellular activities by controlling gene expression, but a predictive model describing how TFs quantitatively modulate human transcriptomes is lacking. We construct a universal human gene expression predictor and utilize it to decode transcriptional regulation. Using the expression of 1613 TFs, the predictor reconstitutes highly accurate transcriptomes for samples derived from a wide range of tissues and conditions. The broad applicability of the predictor indicates that it recapitulates the quantitative relationships between TFs and target genes ubiquitous across tissues. Significant interacting TF-target gene pairs are extracted from the predictor and enable downstream inference of TF regulators for diverse pathways involved in development, immunity, metabolism, and stress response. A detailed analysis of the hematopoiesis process reveals an atlas of key TFs regulating the development of different hematopoietic cell lineages, and a portion of these TFs are conserved between humans and mice. The results demonstrate that our method is capable of delineating the TFs responsible for fate determination. Compared to other existing tools, our approach shows better performance in recovering the correct TF regulators. Thus, we present a novel approach that can be used to study human transcriptional regulation in general.

Among many factors known to alter the outcomes of T cell receptor (TCR)-induced proximal signalling, the role played by human germline variants in dictating the individuality of the anti-tumour CD8 T cell response has remained challenging to address. Here, we describe a convenient strategy for molecular and functional characterization of phosphotyrosine-altering non-synonymous single nucleotide variations (pTyr-SNVs) that directly impact TCR-induced proximal phosphotyrosine motif-based signalling pathways. We devise an experimental co-cultivation set-up comprising a C57BL/6 mouse-derived metastatic melanoma cell line engineered to constitutively present ovalbumin (OVA) antigens and retrovirally engineer syngeneic MHC Class I restricted OVA TCR-transgenic CD8 T cells (OT-I). Using the synthetic version of pTyr-SNV rs1178800678-G/T encoding ITGA4 p.S1027I variant as a prototype, which generates a membrane-proximal immunoreceptor tyrosine activation motif (ITAM), we show that under identical TCR stimulation conditions, genetically determined membrane-proximal ITAM elevates tyrosine phosphorylation of proximal signalling molecule 70 kDa zeta-chain associated protein (ZAP70) and the levels of cytotoxic effector molecule granzyme B (GZMB), thereby contributing to enhanced cytotoxic activity against metastatic melanoma cell line. This strategy paves the way for rapid molecular and functional characterization of anti-tumor immune response-linked germline nsSNVs and uncover the genetic determinants of individual-to-individual differences in anti-tumour CD8 T cell response.

Genetic variation is a key factor influencing cytokine production capacity, but which genetic loci regulate cytokine production before and after vaccination, particularly in African population is unknown. Here, we aimed to identify single-nucleotide polymorphisms (SNPs) controlling cytokine responses (cQTLs) after microbial stimulation in infants of West-African ancestry, comprising of low-birth-weight neonates randomized to BCG vaccine-at-birth (intervention) or to the usual delayed BCG (control). Genome-wide cytokine QTL-mapping revealed 12 independent cQTLs loci, of which the LINC01082-LINC00917 locus influenced more than half of the cytokine-stimulation pairs assessed. Furthermore, nine distinct cQTLs were found among infants randomized to BCG. Functional validation confirmed that several complement genes affect cytokine response after BCG vaccination. We observed limited overlap of common cQTLs between the West-African infants and cohorts of Western European individuals. These data reveal strong population-specific genetic effects on cytokine production and may indicate new opportunities for therapeutic intervention and vaccine development in African populations.

Recently, cilia defects have been proposed to contribute to scoliosis. Here, we demonstrate that Ccdc57 plays an essential role in straightening the body axis of zebrafish by regulating ciliary beating in the brain ventricle (BV). Zygotic ccdc57 (Zccdc57) mutant zebrafish developes scoliosis without significant changes in their bone density and calcification, and the maternal-zygotic ccdc57 (MZccdc57) mutant embryos display curved bodies since the long-pec stage. The expression of ccdc57 is enriched in ciliated tissues and immunofluorescence analysis reveals colocalization of Ccdc57-HA with acetylated α-tubulin, implicating it in having a role in ciliary function. Further examination reveals that it is the coordinated cilia beating of multiple cilia bundles (MCB) in the Mzccdc57 mutant embryos that is affected at 48 hours post fertilization (hpf), when the compromised cerebrospinal fluid (CSF) flow and curved body axis have already occurred. Either ccdc57 mRNA injection or epinephrine treatment reverses the spinal curvature in MZccdc57 mutant larvae from ventrally curly to straight or even dorsally curly and significantly upregulates urotensin signaling. This study reveals the role of ccdc57 in maintaining coordinated cilia beating of MCB in the BV.