Search Results (12)

As the hybrid offspring of cattle and yak, cattle–yaks suffer from male sterility, manifesting as cascading spermatogenic failure. Despite the Y chromosome’s pivotal role in spermatogenesis, the absence of a high-quality yak Y assembly has long impeded mechanistic understandings from this perspective. Here, a near-complete 42.4 Mb yak Y chromosome is constructed through a multi-stage assembly strategy that integrates de novo assembly with pangenome graph construction and Hi-C guided refinement. By developing a rigorously standardized gene annotation pipeline for precise cross-species comparison, we find that yaks have undergone a greater expansion of Y-linked ampliconic genes than cattle. Integrating this ampliconic landscape with short-read and full-length transcriptomics further demonstrates that yaks exhibit a drastic 2-to-4-fold increase in transcriptionally active copies of spermatogenesis-related ampliconic genes (including TSPY1, ZNF280BY, HSFY and PRAMEY) relative to cattle. Given negligible homology outside the pseudoautosomal region and conservation of key meiotic proteins, we propose a ‘cis-trans regulatory mismatch’ model driven by divergent Y-linked amplification as a working hypothesis to explain the primary genetic mechanism of cattle–yak male sterility. Together, these findings offer critical insights for addressing cattle–yak male sterility and establish the Y chromosome as an active driver of reproductive isolation beyond its traditional degenerate characterization. Full article

Glioblastoma (GBM) represents a highly invasive primary malignant tumor within the central nervous system (CNS). Temozolomide (TMZ), a first-line chemotherapy agent for GBM treatment, has significant limitations, including drug resistance, poor water solubility, a short half-life, and notable toxic side effects. The innovation of the TMZ dosage form is pivotal for enhancing its therapeutic efficacy. In this study, solid lipid nanoparticles (SLN) loaded with Angiopep-2 (A2) and TMZ (TMZ-A2SLN), a nanopolymer featuring a solid spherical morphology and a particle size of approximately 100 nm, were constructed. The combined effect of TMZ-A2SLN and small-interfering RNA (siRNA) that can knock down the expression of the HOXB9 gene (siHOXB9) augmented the sensitivity of the glioma cell line U251 to TMZ. Under the combined effect, the viability of U251 cells was reduced by 77%. Meanwhile, the mortality rate increased by approximately 45%, and the cell apoptosis rate rose by around 36%. The number of cells arrested in the G2/M and S phases rose. Proteomic analysis indicates that TMZ-A2SLN might be implicated in the pro-inflammatory signaling cascade, tumor migration, invasion, and angiogenesis during the treatment of glioma cells. Moreover, HOXB9 may play a crucial regulatory role in the PPAR signaling pathway, the neural signaling pathway, the phospholipase D signaling pathway, the IL-17 signaling pathway, mineral absorption, and other pathways during glioma cell treatment. Full article

Genomic imbalance in aneuploidy is often detrimental to organisms. To gain insight into the molecular basis of aneuploidies in humans, we analyzed transcriptome data from several autosomal and sex chromosome aneuploidies. The results showed that in human aneuploid cells, genes located on unvaried chromosomes are inversely or proportionally trans-modulated, while a subset of genes on the varied chromosomes are compensated. Less genome-wide modulation is found for sex chromosome aneuploidy compared with autosomal aneuploidy due to X inactivation and the retention of dosage sensitive regulators on both sex chromosomes to limit the effective dosage change. We also found that lncRNA and mRNA can have different responses to aneuploidy. Furthermore, we analyzed the relationship between dosage-sensitive transcription factors and their targets, which illustrated the modulations and indicates genomic imbalance is related to stoichiometric changes in components of gene regulatory complexes.In summary, this study demonstrates the existence of trans-acting effects and compensation mechanisms in human aneuploidies and contributes to our understanding of gene expression regulation in unbalanced genomes and disease states. Full article

Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene that causes autistic phenotypes when deleted or duplicated. Observations from clinical cases and animal models also suggest that changes of RAI1 expression levels contribute to autism. Previously, we used a bioinformatic approach to identify several single nucleotide polymorphisms (SNPs) located within the 5′-region of RAI1 that correlate with RAI1 mRNA expression in the human brain. In particular, the SNP rs4925102 was identified as a candidate cis-acting regulatory variant, the genotype of which may affect the binding of transcription factors that influence RAI1 mRNA expression. In this study, we provide experimental evidence based on reporter gene, chromatin immunoprecipitation (ChIP), and chromatin conformation capture (3C) assays that rs4925102 regulates RAI1 mRNA expression in an allele-specific manner in human cell lines, including the neuroblastoma-derived cell line SH-SY5Y. We also describe a statistically significant association between rs4925102 genotype and autism spectrum disorder (ASD) diagnosis in a case-control study and near-statistically significant association in an Autism Genome Project (AGP) transmission disequilibrium (TDT) study using Caucasian subjects. Full article

This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment damage. Through genetic analysis and bioinformatic tools, a specific nonsynonymous substitution, p.(Asn114Ser), within the PAX6 gene’s paired domain is identified. Although this substitution is not in direct contact with DNA, its predicted stabilizing effect on the protein structure challenges the traditional understanding of PAX6 mutations, suggesting a gain-of-function mechanism. Contrary to classical loss-of-function effects, this gain-of-function hypothesis aligns with research demonstrating PAX6’s dosage sensitivity. Gain-of-function mutations, though less common, can lead to diverse phenotypes distinct from aniridia. Our findings emphasize PAX6’s multifaceted influence on ocular phenotypes and the importance of genetic variations. We contribute a new perspective on PAX6 mutations by suggesting a potential gain-of-function mechanism and showcasing the complexities of ocular development. This study sheds light on the intricate interplay of the genetic alterations and regulatory mechanisms underlying complex eye phenotypes. Further research, validation, and collaboration are crucial to unravel the nuanced interactions shaping ocular health and development. Full article

The Hedgehog (Hh) signaling pathway plays an essential role in the initiation and progression of prostate cancer. This is mediated by transcriptional factors belonging to the GLI (glioma-associated oncogene) family, which regulate downstream targets to drive prostate cancer progression. The activity of GLI proteins is tightly controlled by a range of mechanisms, including molecular interactions and post-translational modifications. In particular, mitogenic and oncogenic signaling pathways have been shown to regulate GLI protein activity independently of upstream Hh pathway signaling. Identifying GLI protein regulators is critical for the development of targeted therapies that can improve patient outcomes. This study aimed to identify a novel protein that directly regulates the activity of GLI transcription factors in prostate cancer. We performed gene expression, cellular analyses, and reporter assays to demonstrate that DAX1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) interacts with GLI1 and GLI2, the master regulators of Hh signaling. Interestingly, DAX1 overexpression significantly inhibited Hh signaling by reducing GLI1 and GLI2 activity, prostate cancer cell proliferation, and viability. Our results shed light on a novel regulatory mechanism of Hh signaling in prostate cancer cells. The interaction between DAX1 and GLI transcription factors provides insight into the complex regulation of Hh signaling in prostate cancer. Given the importance of Hh signaling in prostate cancer progression, targeting DAX1–GLI interactions may represent a promising therapeutic approach against prostate cancer. Overall, this study provides new insights into the regulation of the Hh pathway and its role in prostate cancer progression. The findings suggest that DAX1 could serve as a potential therapeutic target for the treatment of prostate cancer. Full article

Aneuploidy is usually more detrimental than altered ploidy of the entire set of chromosomes. To explore the regulatory mechanism of gene expression in aneuploidy, we analyzed the transcriptome sequencing data of metafemale Drosophila. The results showed that most genes on the X chromosome undergo dosage compensation, while the genes on the autosomal chromosomes mainly present inverse dosage effects. Furthermore, long noncoding RNAs (lncRNAs) have been identified as key regulators of gene expression, and they are more sensitive to dosage changes than mRNAs. We analyzed differentially expressed mRNAs (DEGs) and differentially expressed lncRNAs (DELs) in metafemale Drosophila and performed functional enrichment analyses of DEGs and the target genes of DELs, and we found that they are involved in several important biological processes. By constructing lncRNA-mRNA interaction networks and calculating the maximal clique centrality (MCC) value of each node in the network, we also identified two key candidate lncRNAs (CR43940 and CR42765), and two of their target genes, Sin3A and MED1, were identified as inverse dosage modulators. These results suggest that lncRNAs play an important role in the regulation of genomic imbalances. This study may deepen the understanding of the gene expression regulatory mechanisms in aneuploidy from the perspective of lncRNAs. Full article

Aneuploidy, which disrupts the genetic balance due to partial genome dosage changes, is usually more detrimental than euploidy variation. To investigate the modulation of gene expression in aneuploidy, we analyzed the transcriptome sequencing data of autosomal and sex chromosome trisomy in Drosophila. The results showed that most genes on the varied chromosome (cis) present dosage compensation, while the remainder of the genome (trans) produce widespread inverse dosage effects. Some altered functions and pathways were identified as the common characteristics of aneuploidy, and several possible regulatory genes were screened for an inverse dosage effect. Furthermore, we demonstrated that dosage changes of inverse regulator Inr-a/pcf11 can produce a genome-wide inverse dosage effect. All these findings suggest that the mechanism of genomic imbalance is related to the changes in the stoichiometric relationships of macromolecular complex members that affect the overall function. These studies may deepen the understanding of gene expression regulatory mechanisms. Full article

Aliivibrio fischeri LuxR and Aliivibrio logei LuxR1 and LuxR2 regulatory proteins are quorum sensing transcriptional (QS) activators, inducing promoters of luxICDABEG genes in the presence of an autoinducer (3-oxo-hexanoyl-l-homoserine lactone). In the Aliivibrio cells, luxR genes are regulated by HNS, CRP, LitR, etc. Here we investigated the role of the luxR expression level in LuxI/R QS system functionality and improved the whole-cell biosensor for autoinducer detection. Escherichia coli-based bacterial lux-biosensors were used, in which Photorhabdus luminescensluxCDABE genes were controlled by LuxR-dependent promoters and luxR, luxR1, or luxR2 regulatory genes. We varied either the dosage of the regulatory gene in the cells using additional plasmids, or the level of the regulatory gene expression using the lactose operon promoter. It was shown that an increase in expression level, as well as dosage of the regulatory gene in biosensor cells, leads to an increase in sensitivity (the threshold concentration of AI is reduced by one order of magnitude) and to a two to threefold reduction in response time. The best parameters were obtained for a biosensor with an increased dosage of luxRA. fischeri (sensitivity to 3-oxo-hexanoyl-l-homoserine lactone reached 30–100 pM). Full article

The female-specific W chromosomes of most Neognathae birds are highly degenerated and gene-poor. Previous studies have demonstrated that the gene repertoires of the Neognathae bird W chromosomes, despite being in small numbers, are conserved across bird species, likely due to purifying selection maintaining the regulatory and dosage-sensitive genes. Here we report the discovery of DNA-based sequence duplications from the Z to the W chromosome in birds-of-paradise (Paradisaeidae, Passeriformes), through sequence transposition. The original transposition involved nine genes, but only two of them (ANXA1 and ALDH1A1) survived on the W chromosomes. Both ANXA1 and ALDH1A1 are predicted to be dosage-sensitive, and the expression of ANXA1 is restricted to ovaries in all the investigated birds. These analyses suggest the newly transposed gene onto the W chromosomes can be favored for their role in restoring dosage imbalance or through female-specific selection. After examining seven additional songbird genomes, we further identified five other transposed genes on the W chromosomes of Darwin’s finches and one in the great tit, expanding the observation of the Z-to-W transpositions to a larger range of bird species, but not all transposed genes exhibit dosage-sensitivity or ovary-biased expression We demonstrate a new mechanism by which the highly degenerated W chromosomes of songbirds can acquire genes from the homologous Z chromosomes, but further functional investigations are needed to validate the evolutionary forces underlying the transpositions. Full article

The transcription factor PAX6 is essential in ocular development in vertebrates, being considered the master regulator of the eye. During eye development, it is essential for the correct patterning and formation of the multi-layered optic cup and it is involved in the developing lens and corneal epithelium. In adulthood, it is mostly expressed in cornea, iris, and lens. PAX6 is a dosage-sensitive gene and it is highly regulated by several elements located upstream, downstream, and within the gene. There are more than 500 different mutations described to affect PAX6 and its regulatory regions, the majority of which lead to PAX6 haploinsufficiency, causing several ocular and systemic abnormalities. Aniridia is an autosomal dominant disorder that is marked by the complete or partial absence of the iris, foveal hypoplasia, and nystagmus, and is caused by heterozygous PAX6 mutations. Other ocular abnormalities have also been associated with PAX6 changes, and genotype-phenotype correlations are emerging. This review will cover recent advancements in PAX6 regulation, particularly the role of several enhancers that are known to regulate PAX6 during eye development and disease. We will also present an updated overview of the mutation spectrum, where an increasing number of mutations in the non-coding regions have been reported. Novel genotype-phenotype correlations will also be discussed. Full article

Cardiac development is an exquisitely regulated process that is sensitive to perturbations in transcriptional activity and gene dosage. Accordingly, congenital heart abnormalities are prevalent worldwide, and are estimated to occur in approximately 1% of live births. Recently, small non-coding RNAs, known as microRNAs, have emerged as critical components of the cardiogenic regulatory network, and have been shown to play numerous roles in the growth, differentiation, and morphogenesis of the developing heart. Moreover, the importance of miRNA function in cardiac development has facilitated the identification of prospective therapeutic targets for patients with congenital and acquired cardiac diseases. Here, we discuss findings attesting to the critical role of miRNAs in cardiogenesis and cardiac regeneration, and present evidence regarding the therapeutic potential of miRNAs for cardiovascular diseases. Full article