Journal of Genetics and Genomics最新文献

Accumulation of mutant proteins in cells can induce proteinopathies and cause functional damage to organs. Recently, the Cingulin (CGN) protein has been shown to maintain the morphology of cuticular plates of inner ear hair cells and a frameshift mutation in CGN causes autosomal dominant non-syndromic hearing loss. Here, we find that the mutant CGN proteins form insoluble aggregates which accumulate intracellularly and lead to cell death. Expression of the mutant CGN in the inner ear results in severe hair cell death and hearing loss in mice, resembling the auditory phenotype in human patients. Interestingly, a human-specific residue (V1112) in the neopeptide generated by the frameshift mutation is critical for the aggregation and cytotoxicity of the mutant human CGN. Moreover, the expression of heat shock factor 1 (HSF1) decreases the accumulation of insoluble mutant CGN aggregates and rescues cell death. In summary, these findings identify mutant-specific toxic polypeptides as a disease-causing mechanism of the deafness mutation in CGN, which can be targeted by the expression of the cell chaperone response regulator HSF1.

Gene therapy has shown significant potential in treating various diseases, particularly inherited blood disorders such as hemophilia, sickle cell disease, and thalassemia. Advances in understanding the regulatory network of disease-associated genes have led to the identification of additional therapeutic targets for treatment, especially for β-hemoglobinopathies. Erythroid regulatory factor BCL11A offers the most promising therapeutic target for β-hemoglobinopathies, and reduction of its expression using the commercialized gene therapy product Casgevy has been approved for use in the UK and USA in 2023. Notably, the emergence of innovative gene editing technologies has further broadened the gene therapy landscape, presenting possibilities for treatment. Intensive studies indicate that base editing and prime editing, built upon CRISPR technology, enable precise single-base modification in hematopoietic stem cells for addressing inherited blood disorders ex vivo and in vivo. In this review, we present an overview of the current landscape of gene therapies, focusing on clinical research and gene therapy products for inherited blood disorders, evaluation of potential gene targets, and the gene editing tools employed in current gene therapy practices, which provides an insight for the establishment of safer and more effective gene therapy methods for a wider range of diseases in the future.

Human UDP-glycosyltransferases (UGTs) are responsible for the glycosylation of a wide variety of endogenous substrates and commonly prescribed drugs. Different genetic polymorphisms in UGT genes are implicated in interindividual differences in drug response and cancer risk. However, the genetic complexity beyond these variants has not been comprehensively assessed. We here leveraged whole-exome and whole-genome sequencing data from 141,456 unrelated individuals across 7 major human populations to provide a comprehensive profile of genetic variability across the human UGT gene family. Overall, 9666 exonic variants were observed, of which 98.9% were rare. To interpret the functional impact of UGT missense variants, we developed a gene family-specific variant effect predictor. This algorithm identified a total of 1208 deleterious variants, most of which were found in African and South Asian populations. Structural analysis corroborated the predicted effects for multiple variations in substrate binding sites. Combined, our analyses provide a systematic overview of UGT variability, which can yield insights into interindividual differences in phase 2 metabolism and facilitate the translation of sequencing data into personalized predictions of UGT substrate disposition.

Zebrafish embryos possess two major types of myofibers, the slow and fast fibers, with distinct patterns of cell fusion. The fast muscle cells can fuse, while the slow muscle cells cannot. Here, we show that myomaker is expressed in both slow and fast muscle precursors, whereas myomixer is exclusive to fast muscle cells. The loss of Prdm1a, a regulator of slow muscle differentiation, results in strong myomaker and myomixer expression and slow muscle cell fusion. This abnormal fusion is further confirmed by the direct ectopic expression of myomaker or myomixer in slow muscle cells of transgenic models. Using the transgenic models, we show that the heterologous fusion between slow and fast muscle cells can alter slow muscle cell migration and gene expression. Furthermore, the overexpression of myomaker and myomixer also disrupts membrane integrity, resulting in muscle cell death. Collectively, this study identifies that the fiber-type-specific expression of fusogenic proteins is critical for preventing inappropriate fusion between slow and fast fibers in fish embryos, highlighting the need for precise regulation of fusogenic gene expression to maintain muscle fiber integrity and specificity.

Dendritic morphology is typically highly branched, and the branching and synaptic abundance of dendrites can enhance the receptive range of neurons and the diversity of information received, thus providing the basis for information processing in the nervous system. Once dendritic development is aberrantly compromised or damaged, it may lead to abnormal connectivity of the neural network, affecting the function and stability of the nervous system and ultimately triggering a series of neurological disorders. Research on the regulation of dendritic developmental processes has flourished, and much progress is now being made in its regulatory mechanisms. Noteworthily, dendrites are characterized by an extremely complex dendritic arborization that cannot be attributed to individual protein functions alone, requiring a systematic analysis of the intrinsic and extrinsic signals and the coordinated roles among them. Actin cytoskeleton organization and membrane vesicle trafficking are required during dendrite development, with actin providing tracks for vesicles and vesicle trafficking in turn providing material for actin assembly. In this review, we focus on these two basic biological processes and discuss the molecular mechanisms and their synergistic effects underlying the morphogenesis of neuronal dendrites. We also offer insights and discuss strategies for the potential preventive and therapeutic treatment of neuropsychiatric disorders.

Cold stress in low-temperature environments can trigger changes in gene expression, but epigenomics regulation of temperature stability in vital tissues, including the fat and diencephalon, is still unclear. Here, we explore the cold-induced changes in epigenomic features in the diencephalon and fat tissues of two cold-resistant Chinese pig breeds, Min and Enshi black (ES) pigs, utilizing H3K27ac CUT&Tag, RNA-seq, and selective signature analysis. Our results show significant alterations in H3K27ac modifications in the diencephalon of Min pigs and the fat of ES pigs after cold exposure. Dramatic changes in H3K27ac modifications in the diencephalon of Min pig are primarily associated with genes involved in energy metabolism and hormone regulation, whereas those in the fat of ES pig are primarily associated with immunity-related genes. Moreover, transcription factors PRDM1 and HSF1, which show evidence of selection, are enriched in genomic regions presenting cold-responsive alterations in H3K27ac modification in the Min pig diencephalon and ES pig fat, respectively. Our results indicate the diversity of epigenomic response mechanisms to cold exposure between Min and ES pigs, providing unique epigenetic resources for studies of low-temperature adaptation in large mammals.