Genomics, proteomics & bioinformatics最新文献

The forebrain regions display distinct yet under-characterized gene expression patterns. In this study, we analyzed region-specific feature genes in forebrain regions and Isocortex subregions at both the transcriptomic and proteomic levels. The key finding was the observation of a low correlation but high functional similarity between mRNA and protein expression, providing new insights into the relationship between gene expression forms in neuronal pathways and the neuronal activity states. Cholinergic neurons (CNs) play a vital role in forebrain sensory and motor regulation. With Spatial-transcriptome and immunofluorescence joint analysis (STIF), which overcomes the resolution limitations of the 10X Visium system, we identified CNs and CN-subtypes specific feature genes in the striatum and basal forebrain, providing crucial insights into the heterogeneity and functional diversity of these neuronal populations. The spatial distribution and expression patterns of the identified feature genes were validated using either external datasets or rolling circle amplification fluorescence in situ hybridization (RCA-FISH), coincident results were revealed.

RNA structures are essential building blocks of functional RNA molecules. Profiling secondary structures in vivo and in real time remains challenging because RNAs exhibit dynamic structures and complex conformations. Besides the canonical stem-loop secondary structure, non-canonical structure RNA G-quadruplex (rG4) has attracted interest for its potential as a drug target. Early studies have demonstrated that RNAs can form distinct secondary structures. However, how distinct RNA structures, formed from the same RNA sequences, function within the transcriptome is poorly understood, and factors driving and regulating structure transitions remain to be investigated. Inspired by an HOXB9 segment able to form multiple structures, we found that many RNA segments across the transcriptome exhibit multi-faceted structure-forming potential. In the case of HOXB9, we demonstrate that N6-methyladenosine (m6A) modification influences RNA structure and binding to RNA-binding proteins (RBPs). Therefore, we collected RNA modification sites naturally occurring within the putative G-quadruplex-forming sequences (PQSs) of transcripts and developed MoRNiNG, a database for RNA modifications in natural rG4. MoRNiNG is structured with reliability tiers determined by the resolution of RNA modification sites and is designed to accommodate various large datasets. We experimentally validated the influence of m6A, 5-methylcytosine (m5C), and adenosine to inosine (A-to-I) editing on rG4-forming sequences, providing evidence to support the modification switch concept. The diversity and transition of secondary structures from the same RNA segment offer valuable insights into the regulation of RNA structure dynamics. MoRNiNG is freely accessible at https://www.cityu.edu.hk/bms/morning.

RNA splicing is pivotal in neural development, yet the role of isoform diversity across cell types remains unclear. Here, we combined metabolic RNA labeling and single-cell full-length transcriptome sequencing to capture transcriptional dynamics in developing mouse cortices. We observed predetermined cell states supported by nascent RNAs and characterized the driving isoforms of transcription factors that regulated the development of deep- and upper-layer neurons. Additionally, we investigated isoform regulation associated with autism spectrum disorder (ASD) during the embryonic development of BTBR T  +  Itpr3tf mice. Our findings indicated premature emergence of callosal projection neurons (CPNs) with an immature identity in ASD-affected cortices. These CPNs exhibited abnormal transcript usage, and the related RNA binding proteins included nearly 60% that have been reported to be ASD risk genes. We identified isoform switching events modulating neurogenesis and ASD development. Finally, we observed reduced isoform diversity in ASD potentially linked to dysregulated H3K27ac levels. Collectively, our study represents a significant advancement in understanding the molecular basis of cortical development and functions.

Human populations have substantial genetic diversity, but the extent of epigenetic diversity remains unclear, as population-specific DNA methylation (DNAm) has only been studied for ∼3.0% of CpGs. This study quantifies DNAm using whole-genome bisulfite sequencing (WGBS) and analyzes it alongside whole-genome genotype data to reveal a comprehensive picture of population-specific DNAm. Using a "co-methylated region" (CMR) approach, 36,657 CMRs were identified in 62 lymphoblastoid B cell line (LCL) WGBS samples, with validation in array data sets from 326 LCL samples. Between individuals of European and African ancestry, 101 CMRs exhibited population-specific DNAm patterns (Pop-CMRs), including 91 Pop-CMRs not found in previous investigations, which spanned genes (e.g., CCDC42, GYPE, MAP3K20, and OBI1) related to diseases (e.g., malaria infection and diabetes) with different prevalence and incidence rates between populations. Over half of the Pop-CMRs were asscoated with genetic variants, displaying population-specific allele frequencies and primarily mapping to genes involved in metabolic and infectious processes. Additionally, subsets of Pop-CMRs could be applicable in East Asian populations and peripheral blood-based tissues. This study provides insights into DNAm differences across the genome between populations and explores their associations with genetic variants and biological relevance, advancing our understanding of epigenetic roles in population specificity.

Neoantigens are classified into canonical and noncanonical types. Noncanonical neoantigens include those derived from noncoding regions, transposable elements (TE), and intron retention events, and they have recently gained considerable attention in cancer immunity. In this study, we focused on neoantigens presented by HLA class I molecules, which are central to CD8+ T cell-mediated immune responses. We curated 39,347 non-redundant neoantigen-HLA pairs from 14 immunopeptidomes studies, by analyzing unique features and differences across various sources of neoantigens. This knowledge enabled us to develop machine learning models for the prediction of different types of neoantigens. Our data and models are available at a public portal (https://ngdc.cncb.ac.cn/neoatlas) to facilitate broad access and future research. This resource offers advanced functionalities, including integration with epigenome browsers which allow easy navigation of epigenomic datasets to support and confirm the expression of neoantigens. We further demonstrate that combining our database with mass spectrometry analysis can identify noncanonical neoantigens. The resource we constructed holds significant value and promise for the development of neoantigen-based vaccines. All data, machine learning models, and analytical tools are freely available at the NeoAtlas-Tumor portal (https://ngdc.cncb.ac.cn/neoatlas).

We conducted a comprehensive genetic investigation of obesity in a cohort of 93,673 Korean individuals, categorized by body mass index and waist circumference using Korean-specific and international criteria. To explore the genetic architecture of obesity and its related comorbidities, we performed genome-wide association studies and constructed polygenic risk scores (PRSs) using both conventional single-trait and advanced multiple-trait models, including the PRSsum approach. Our analyses identified genome-wide significant loci and demonstrated higher heritability for general obesity than for abdominal obesity, and for moderate obesity than for severe obesity. East Asian populations showed stronger genetic correlations between abdominal obesity and obesity-related diseases. Both single-trait and multiple-trait PRSs stratified individuals by risk, with low PRS individuals exhibiting reduced risk for obesity, hypertension, and type 2 diabetes, while high PRS individuals displayed elevated risk, particularly under the multiple-trait model. Interaction and mediation analyses revealed distinct genetic pathways through which obesity contributes to disease development. Collectively, our findings revealed key loci and shared genetic mechanisms linking obesity and its comorbidities in the Korean population. These insights highlight the value of multiple-trait PRS models and underscore the importance of ancestry-specific genetic research for addressing the obesity epidemic.

The use of statins as the primary therapy for reducing low-density lipoprotein cholesterol has raised concerns regarding their potential side effects in increasing the risk of type 2 diabetes (T2D). However, the underlying mechanism remains largely unknown. In this study, we utilized multi-omics molecular signatures to unravel the etiology of statin-induced T2D. Through systematic screening of 102 gut microbial features, 40 blood metabolites, and 131 circulating proteins in East Asians and Europeans, we identified a set of blood metabolites and proteins potentially influenced by genetically proxied statin use. Notably, Mendelian randomization analyses provided evidence that elevated circulating levels of gastric inhibitory polypeptide (GIP) were associated with an increased risk of T2D. This association between genetically proxied statin use and GIP was consistently observed across East Asian and European populations, highlighting the pivotal role of GIP in modulating the risks of statin-induced T2D. Furthermore, this study establishes an extensive atlas of multi-omics molecular signatures associated with statin-induced T2D, offering valuable insights for prioritizing intervention targets.

The ultimate goal of a genome-wide association study (GWAS) is to translate its discoveries into clinical practice. To explore the clinical use of GWAS findings in the bone field, we conducted a GWAS of dual-energy X-ray absorptiometry (DXA)-derived bone mineral density (BMD) traits at 11 skeletal sites, within over 30,000 European individuals from the UK Biobank. A total of 91 unique and independent loci were identified for 11 DXA-derived BMD traits and fractures, including five novel loci (harboring the genes ABCA1, CHSY1, CYP24A1, SWAP70, and PAX1) for six BMD traits. These loci exhibited evidence of association in both males and females, which could serve as independent replication. We demonstrated that each polygenic risk score (PRS) was independently associated with fracture risk. Although incorporating multiple PRSs (ie, metaPRS) with clinical risk factors from the Fracture Risk Assessment Tool exhibited the highest predictive performance, the improvement was modest in fracture prediction. Additionally, we uncovered genetic correlation and shared polygenicity between head BMD and intracranial aneurysm. Finally, by integrating gene expression and GWAS datasets, we prioritized genes (e.g., ESR1 and SREBF1) encoding druggable human proteins along with their respective inhibitors/antagonists. In conclusion, this comprehensive investigation revealed a new genetic basis for BMD and its clinical relevance to fracture prediction. More importantly, it is suggested that head BMD was genetically correlated with intracranial aneurysm. The prioritization of genetically supported targets implies the potential repurposing of drugs (e.g., the n-3 PUFA supplement) for the prevention of osteoporosis.

Tumor heterogeneity and the suppressive microenvironment are key challenges that limit the effectiveness of cancer treatment. In this study, we systematically elucidated the molecular characteristics and mechanisms underlying the suppressive immune microenvironment via a combination of single-cell RNA sequencing, spatial transcriptomics, and metabolomics for a series of human esophageal squamous cell carcinoma (ESCC) and matched nontumor tissues. We found that COL17A1+ epithelial cells presented greater malignancy, characterized by triglyceride (TG) and phosphocholine (PC) accumulation. We also identified a tumor-specific POSTN+ fibroblast subgroup. We found a unique epithelial-fibroblast niche with low infiltration of effector immune cells and substantial enrichment of lipids, composed of POSTN+ fibroblasts and COL17A1+ epithelial cells, where their crosstalk contributed to tumor progression. We confirmed that the INHBA/TP63 axis played a key role in mediating the regulation of COL17A1+ tumor cells by POSTN+ fibroblasts. Our findings provide new insights into the characteristics of the tumor microenvironment and the crosstalk between tumor and fibroblasts, offering valuable multiomics data resources for elucidating tumor progression mechanisms.