Construction of a molecular inflammatory predictive model with histone modification-related genes and identification of CAMK2D as a potential response signature to infliximab in ulcerative colitis.

Background: Ulcerative colitis (UC) is a lifelong inflammatory disease affecting the rectum and colon with numerous treatment options that require an individualized treatment plan. Histone modifications regulate chromosome structure and gene expression, resulting in effects on inflammatory and immune responses. However, the relationship between histone modification-related genes and UC remains unclear. Methods: Transcriptomic data from GSE59071 and GSE66407 were obtained from the Gene Expression Omnibus (GEO), encompassing colonic biopsy expression profiles of UC patients in inflamed and non-inflamed status. Differentially expressed gene (DEG) analyses, functional enrichment analyses, weighted gene co-expression network analysis (WGCNA), and random forest were performed to identify histone modification-related core genes associated with UC inflammation. Features were screened through the least absolute shrinkage and selection operator (LASSO) and support vector machine-recursive feature elimination (SVM-RFE), establishing a molecular inflammatory predictive model using logistic regression. The model was validated in the GSE107499 dataset, and the performance of the features was assessed using receiver operating characteristic (ROC) and calibration curves. Immunohistochemistry (IHC) staining of colonic biopsy tissues from UC patients treated with infliximab was used to further confirm the clinical application value. Univariate logistic regression on GSE14580 highlighted features linked to infliximab response. Results: A total of 253 histone modification-related DEGs were identified between inflammatory and non-inflammatory patients with UC. Seven key genes (IL-1ß, MSL3, HDAC7, IRF4, CAMK2D, AUTS2, and PADI2) were selected using WGCNA and random forest. Through univariate logistic regression, three core genes (CAMK2D, AUTS2, and IL-1ß) were further incorporated to construct the molecular inflammatory predictive model. The area under the curve (AUC) of the model was 0.943 in the independent validation dataset. A significant association between CAMK2D protein expression and infliximab response was observed, which was validated in another independent verification set of GSE14580 from the GEO database. Conclusion: The molecular inflammatory predictive model based on CAMK2D, AUTS2, and IL-1ß could reliably distinguish the mucosal inflammatory status of UC patients. We further revealed that CAMK2D was a predictive marker of infliximab response. These findings are expected to provide a new evidence base for personalized treatment and management strategies for UC patients.

De novo variants in genes regulating stress granule assembly associate with neurodevelopmental disorders.

Stress granules (SGs) are cytoplasmic assemblies in response to a variety of stressors. We report a new neurodevelopmental disorder (NDD) with common features of language problems, intellectual disability, and behavioral issues caused by de novo likely gene-disruptive variants in UBAP2L, which encodes an essential regulator of SG assembly. Ubap2l haploinsufficiency in mouse led to social and cognitive impairments accompanied by disrupted neurogenesis and reduced SG formation during early brain development. On the basis of data from 40,853 individuals with NDDs, we report a nominally significant excess of de novo variants within 29 genes that are not implicated in NDDs, including 3 essential genes (G3BP1, G3BP2, and UBAP2L) in the core SG interaction network. We validated that NDD-related de novo variants in newly implicated and known NDD genes, such as CAPRIN1, disrupt the interaction of the core SG network and interfere with SG formation. Together, our findings suggest the common SG pathology in NDDs.

Structural characterization of immune receptor family short pentraxins, C-reactive protein and serum amyloid P component, in primates.

The short pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are a family of pattern-recognition molecules that play versatile roles in innate immunity and inflammation. A comprehensive description is currently lacking as to the genetic characteristics of these molecules in primates. In the present study, we analyzed genetic changes of CRP and SAP genes in this phylogenic lineage. The results revealed that adaptive selection has brought about interspecific diversities of both genes. The adaptively selected amino acid changes have occurred in or adjacent to the structural domains involved in ligand- and effector-binding and homologous aggregation. Each gene, however, exhibits a striking lack of genetic variation in both commonly-used non-human primate models Macaca fascicularis and M. mulatta. These findings highlight basic facts on the genetic characteristics of primate short pentraxins and would contribute powerfully to the extrapolation of their functional insights and physiological outcomes from primate models to humans.

Genetic characterization of nuclear export factor NXT1 and its paralog NXT2 in primates and murine rodents.

Translocation of RNA across the nuclear envelope relies on transport receptors. Receptor nuclear transport factor 2 (NTF2)-like export protein 1 (NXT1 [also called p15 or p15-1]) shuttles between the nucleus and cytoplasm of metazoan cells and contributes to the nuclear export of a diverse spectrum of RNAs. NXT2 (also called p15-2), a paralog of NXT1 in eutherians, also has implications for RNA nuclear export. A comprehensive description is currently lacking as to the genetic signature of these molecules. In this study, we analyzed genetic changes in the NXT1 and NXT2 genes in primates and murine rodents, including the commonly used model organisms Macaca spp., Mus musculus, and Rattus norvegicus. The results show that NXT1 has been subject to functional constraints in both phylogenetic lineages. Conversely, NXT2 exhibits discrepant patterns of genetic changes between these taxa. Murine NXT2 has evolved conservatively; by contrast, adaptive selection has frequently contributed to genetic changes in primate NXT2. The genetic discrepancy of the NXT2 orthologs leads to the suggestion that they had experienced quite different evolutionary fates potentially constituting different functional implementations in these taxa. These findings raise awareness of further study on different organisms to comprehensively understand their functional characteristics.

Genetic diversification of chemokine CXCL16 and its receptor CXCR6 in primates.

Chemokine CXCL16 and its receptor CXCR6 are associated with a series of physiological and pathological processes in cooperative and stand-alone fashions. To shed insight into their versatile nature, we studied genetic variations of CXCL16 and CXCR6 in primates. Evolutionary analyses revealed that these genes underwent a similar evolutionary fate. Both genes experienced adaptive diversification with the phylogenetic division of cercopithecoids (Old World monkeys) and hominoids (humans, great apes, and gibbons) from their common ancestor. In contrast, they were conserved in the periods preceding and following the dividing process. In terms of the adaptive diversification between cercopithecoids and hominoids, the adaptive genetic changes have occurred in the mucin-like and chemokine domains of CXCL16 and the N-terminus and transmembrane helixes of CXCR6. In combination with currently available structural and functional information for CXCL16 and CXCR6, the parallels between the evolutionary footprints and the co-occurrence of adaptive diversification at some evolutionary stage suggest that interplay could exist between the diversification-related amino acid sites, or between the domains on which the identified sites are located, in physiological processes such as chemotaxis and/or cell adhesion.