OsOFP6 Overexpression Alters Plant Architecture, Grain Shape, and Seed Fertility.

OVATE family proteins (OFPs) play important roles in plant growth and development, hormone signaling, and stress response pathways. However, the functions of OsOFPs in rice are largely unknown. In this study, a novel gain-of-function rice mutant, Osofp6-D, was identified. This mutant exhibited decreased plant height, erect leaves, reduced panicle size, short and wide seeds, delayed seed germination time, and reduced fertility. These phenotypic changes were attributed to the increased expression of OsOFP6, which was caused by a T-DNA insertion. Complementation of the Osofp6-D phenotype by knockout of OsOFP6 using the CRISPR/Cas9 system confirmed that the Osofp6-D phenotype was caused by OsOFP6 overexpression. In addition, transgenic plants overexpressing OsOFP6 with the 35S promoter mimicked the Osofp6-D phenotype. Cytological observations of the glumes showed that OsOFP6 overexpression altered the grain shape, mainly by altering the cell shape. Hormone response experiments showed that OsOFP6 was involved in the gibberellin (GA) and brassinolide (BR) signaling responses. Further studies revealed that OsOFP6 interacts with E3BB, which is orthologous to the Arabidopsis central organ size-control protein BIG BROTHER (BB). This study further elucidates the regulation mechanism of the rice OFP family on plant architecture and grain shape.

A multi-cohort study of the hippocampal radiomics model and its associated biological changes in Alzheimer's Disease.

There have been no previous reports of hippocampal radiomics features associated with biological functions in Alzheimer's Disease (AD). This study aims to develop and validate a hippocampal radiomics model from structural magnetic resonance imaging (MRI) data for identifying patients with AD, and to explore the mechanism underlying the developed radiomics model using peripheral blood gene expression. In this retrospective multi-study, a radiomics model was developed based on the radiomics discovery group (n = 420) and validated in other cohorts. The biological functions underlying the model were identified in the radiogenomic analysis group using paired MRI and peripheral blood transcriptome analyses (n = 266). Mediation analysis and external validation were applied to further validate the key module and hub genes. A 12 radiomics features-based prediction model was constructed and this model showed highly robust predictive power for identifying AD patients in the validation and other three cohorts. Using radiogenomics mapping, myeloid leukocyte and neutrophil activation were enriched, and six hub genes were identified from the key module, which showed the highest correlation with the radiomics model. The correlation between hub genes and cognitive ability was confirmed using the external validation set of the AddneuroMed dataset. Mediation analysis revealed that the hippocampal radiomics model mediated the association between blood gene expression and cognitive ability. The hippocampal radiomics model can accurately identify patients with AD, while the predictive radiomics model may be driven by neutrophil-related biological pathways.

Contactin-associated protein-like 2 (CNTNAP2) mutations impair the essential α-secretase cleavages, leading to autism-like phenotypes.

Mutations in the Contactin-associated protein-like 2 (CNTNAP2) gene are associated with autism spectrum disorder (ASD), and ectodomain shedding of the CNTNAP2 protein plays a role in its function. However, key enzymes involved in the C-terminal cleavage of CNTNAP2 remain largely unknown, and the effect of ASD-associated mutations on this process and its role in ASD pathogenesis remain elusive. In this report we showed that CNTNAP2 undergoes sequential cleavages by furin, ADAM10/17-dependent α-secretase and presenilin-dependent γ-secretase. We identified that the cleavage sites of ADAM10 and ADAM17 in CNTNAP2 locate at its C-terminal residue I79 and L96, and the main α-cleavage product C79 by ADAM10 is required for the subsequent γ-secretase cleavage to generate CNTNAP2 intracellular domain (CICD). ASD-associated CNTNAP2 mutations impair the α-cleavage to generate C79, and the inhibition leads to ASD-like repetitive and social behavior abnormalities in the Cntnap2-I1254T knock-in mice. Finally, exogenous expression of C79 improves autism-like phenotypes in the Cntnap2-I1254T knock-in and Cntnap2-/- knockout mice. This data demonstrates that the α-secretase is essential for CNTNAP2 processing and its function. Our study indicates that inhibition of the cleavage by pathogenic mutations underlies ASD pathogenesis, and upregulation of its C-terminal fragments could have therapeutical potentials for ASD treatment.

Landscape of enhancer disruption and functional screen in melanoma cells.

BACKGROUND: The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma. RESULTS: Here, we leveraged 297 melanoma whole-genome sequencing samples to prioritize highly recurrent regions. By performing a genome-scale CRISPR interference (CRISPRi) screen on highly recurrent region-associated enhancers in melanoma cells, we identified 66 significant hits which could have tumor-suppressive roles. These functional enhancers show unique mutational patterns independent of classical significantly mutated genes in melanoma. Target gene analysis for the essential enhancers reveal many known and hidden mechanisms underlying melanoma growth. Utilizing extensive functional validation experiments, we demonstrate that a super enhancer element could modulate melanoma cell proliferation by targeting MEF2A, and another distal enhancer is able to sustain PTEN tumor-suppressive potential via long-range interactions. CONCLUSIONS: Our study establishes a catalogue of crucial enhancers and their target genes in melanoma growth and progression, and illuminates the identification of novel mechanisms of dysregulation for melanoma driver genes and new therapeutic targeting strategies.

An autoimmune pleiotropic SNP modulates IRF5 alternative promoter usage through ZBTB3-mediated chromatin looping.

Genetic sharing is extensively observed for autoimmune diseases, but the causal variants and their underlying molecular mechanisms remain largely unknown. Through systematic investigation of autoimmune disease pleiotropic loci, we found most of these shared genetic effects are transmitted from regulatory code. We used an evidence-based strategy to functionally prioritize causal pleiotropic variants and identify their target genes. A top-ranked pleiotropic variant, rs4728142, yielded many lines of evidence as being causal. Mechanistically, the rs4728142-containing region interacts with the IRF5 alternative promoter in an allele-specific manner and orchestrates its upstream enhancer to regulate IRF5 alternative promoter usage through chromatin looping. A putative structural regulator, ZBTB3, mediates the allele-specific loop to promote IRF5-short transcript expression at the rs4728142 risk allele, resulting in IRF5 overactivation and M1 macrophage polarization. Together, our findings establish a causal mechanism between the regulatory variant and fine-scale molecular phenotype underlying the dysfunction of pleiotropic genes in human autoimmunity.