Gene最新文献

Circular RNAs (circRNAs) are post-transcriptional regulators generated from backsplicing of pre-mRNAs of host genes. A major circRNA regulatory mechanism involves microRNA (miRNA) sequestering, relieving miRNA-blocked mRNAs for translation and functions. To investigate possible circRNA-host gene relationship, skeletal myogenesis is chosen as a study model for its developmental importance and for readily available muscle tissues from farm animals for studies at different myogenic stages. This review aims to provide an integrated interpretations on methodologies, regulatory mechanisms and possible host gene-circRNA synergistic functional relationships in skeletal myogenesis, focusing on myoblast differentiation and proliferation, core drivers of muscle formation in myogenesis, while other myogenic processes that play supportive roles in the structure, maintenance and function of muscle tissues are also briefly discussed. On literature review,thirty-two circRNAs derived from thirty-one host genes involved in various myogenic stages are identified; twenty-two (68.6 %) of these circRNAs regulate myogenesis by sequestering miRNAs to engage PI3K/AKT and other signaling pathways while four (12.5 %) are translated into proteins for functions. In circRNA-host gene relationship,ten (32.3 %) host genes are shown to regulate myogenesis,nine (29.0 %) are specific to skeletal muscle functions,and twelve (38.8 %) are linked to skeletal muscle disorders.Our analysis of skeletal myogenesis suggests that circRNAs and host genes act synergistically to regulate cellular functions. Such circRNA-host gene functional synergism may also be found in other major cellular processes. CircRNAs may have evolved later than miRNAs to counteract the suppressive effects of miRNAs and to augment host gene functions to further fine-tune gene regulation.

Background: Lactylation plays an important role in tumor progression. This study aimed to clarify the impact of lactylation on cancer-associated fibroblasts(CAFs).

Methods: Single-cell and bulk RNA sequence data, along with survival information, were obtained from TCGA and GEO datasets. Significant lactylation-associated genes were acquired by differential analysis and used to construct a prognostic model via Cox and LASSO regression analyses. Next, single-cell analysis, enrichment and pathway analysis, pseudotemporal trajectory and survival analysis were used to identify significant lactylation-associated fibroblast subclusters in colon cancer. IMvigor210 and PRJEB23709 cohorts were applied to assess the response to immunotherapy. In vitro experiments were conducted to explore how lactylation affect fibroblasts.

Results: We established a lactylation-associated prognostic model with 17 risk genes in TCGA and further validated it in GEO datasets. Single-cell analysis revealed the lactylation level of fibroblasts in colon cancer was greater than that in normal tissues. Moreover, five lactylation-associated fibroblast subclusters were identified via the NMF algorithm. Patients with lower scores of FB_2_CALD1, FB_3_TPM4 and FB_4_AHNAK subclusters had better clinical prognosis in colon cancer and were more likely to benefit from immunotherapy. Further experiments demonstrated that lactylation could enhance the proliferation, migration and invasion ability of fibroblasts and up-regulate the expression of COL1A1, which was similar to the effect of colon cancer cells.

Conclusion: This study identified key fibroblast subclusters with prognostic value and implied that lactylation might help transform fibroblasts into CAFs in colon cancer for the first time, which provides new paths for understanding the evolution of CAFs and cancer therapeutic strategies.

Background: KLHL24 (Kelch-like protein 24) is a significant component of the ubiquitin-proteasome system (UPS), involved in regulating protein turnover through targeted ubiquitination and degradation. Germline mutations in KLHL24 gene have been known to cause Epidermolysis Bullosa Simplex characterized by skin fragility but has recently been found to cause Cardiomyopathy.

Main body: Various cardiomyopathies, including hypertrophic cardiomyopathy and dilated cardiomyopathy, leading to abnormal protein degradation and affecting the stability and function of essential cardiac proteins which finally results into structural and functional abnormalities in cardiac muscle. In this review, in order to understand the disease association of germline mutations of KLHL24, we summarize all the studies performed with KLHL24 gene including studies from 2016 when KLHL24 was first identified to be associated with epidermolysis bullosa simplex till the recent studies in 2024 by using keywords such as KLHL24 gene, hypertrophic cardiomyopathy, dilated cardiomyopathy and epidermolysis bullosa simplex. Furthermore, we explored the proposed molecular mechanisms and pathophysiologies of KLHL24 associated diseases. Patients with KLHL24 mutations were usually presented with variable clinical symptoms. The main clinical presentations have been cutaneous lesions, cardiac symptoms associated with cardiomyopathies and there have been reports of skeletal muscle weakness and neurological symptoms as well. Current treatments focus on managing clinical symptoms and preventing complications through medications, lifestyle changes, and surgical interventions. In addition, researches have also been conducted cell culture based in vitro studies for reducing the clinical symptoms of KLHL24 associated diseases. However, currently there are no specific clinical trials going on regarding the therapeutic strategies among patients with KLHL24 mutations. Understanding the role of KLHL24 in cardiomyopathies is very important for developing targeted diagnostic approach with therapeutic strategies.

Conclusion: This review emphasizes the importance of KLHL24 mutations as a newly recognized cause of cardiomyopathy, paving the way for improved clinical diagnosis, targeted therapies, and ultimately, for better patient outcomes.

The basis of all improvement in (re)production performance of animals and plants lies in the genetic variation. The underlying genetic variation can be further explored through investigations using molecular markers including single nucleotide polymorphism (SNP) and microsatellite, and more recently structural variants like copy number variations (CNVs). Unlike SNPs, CNVs affect a larger proportion of the genome, making them more impactful vis-à-vis variation at the phenotype level. They significantly contribute to genetic variation and provide raw material for natural and artificial selection for improved performance. CNVs are characterized as unbalanced structural variations that arise from four major mechanisms viz., non-homologous end joining (NHEJ), non-allelic homologous recombination (NAHR), fork stalling and template switching (FoSTeS), and retrotransposition. Various detection methods have been developed to identify CNVs, including molecular techniques and massively parallel sequencing. Next-generation sequencing (NGS)/high-throughput sequencing offers higher resolution and sensitivity, but challenges remain in delineating CNVs in regions with repetitive sequences or high GC content. High-throughput sequencing technologies utilize different methods based on read-pair, split-read, read depth, and assembly approaches (or their combination) to detect CNVs. Read-pair based methods work by mapping discordant reads, while the read-depth approach works on detecting the correlation between read depth and copy number of genetic segments or a gene. Split-read methods involve mapping segments of reads to different locations on the genome, while assembly methods involve comparing contigs to a reference or de novo sequencing. Similar to other marker-trait association studies, CNV-association studies are not uncommon in humans and farm animals. Soon, extensive studies will be needed to deduce the unique evolutionary trajectories and underlying molecular mechanisms for targeted genetic improvements in different farm animal species. The present review delineates the importance of CNVs in genetic studies, their generation along with programs and principles to efficiently identify them, and finally throw light on the existing literature on studies in farm animal species vis-à-vis CNVs.

WRKY transcription factors (TFs) play crucial roles in responses to abiotic and biotic stresses that significantly impact plant growth and development. Advancements in molecular biology and sequencing technologies have elevated WRKY TF studies from merely determining expression patterns and functional characterization to uncovering molecular regulatory networks. Numerous WRKY TFs regulate drought tolerance in plants through various regulatory networks. This review details the physiological and molecular mechanisms of WRKY TFs regulating drought tolerance. The review focuses on the WRKY TFs involved in the phytohormone and metabolic pathways associated with the drought stress response and the multiple functions of these WRKY TFs, including biotic and abiotic stress responses and their participation in plant growth and development.

The G0/G1 switch gene 2 (G0s2) is a selective inhibitor of adipose triglyceride lipase (ATGL) which is the rate-limiting enzyme for triglycerides (TGs) hydrolysis in adipocytes, and regulates the mobilization of TGs in adipocytes and hepatocytes. The expression and functional disorders of G0S2 are associated with various metabolic diseases and related pathological states, such as obesity and metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). However, the extent to which the transcriptional regulatory mechanisms mediated by the interaction between the G0s2 gene promoter and enhancer regions are involved remains unknown. Here, through the analysis of epigenomic data (H3K27ac, H3K4me1, and DHS-seq) and luciferase reporter assays, we identified three active enhancers of G0s2 in 3 T3-L1 adipocytes. Subsequently, using the dCas9-KRAB system for epigenetic inhibition of G0S2-En2, -En4, and -En5 revealed the functional role of these enhancers in regulating G0s2 expression and lipid droplet biosynthesis. Additionally, transcriptome analyses revealed that inhibition of G0S2-En5 downregulated pathways associated with lipid metabolism and lipid biosynthesis. Furthermore, overexpression of transcription factors (TFs) and motif mutation experiments identified that PPARG and RXRA regulate the activity of G0S2-En5. Taken together, we identified functional enhancers regulating G0s2 expression and elucidated the important role of the G0S2-En5 in lipid droplet biogenesis.

Background: Diabetic nephropathy (DN) is one of the most common and serious microvascular complications associated with diabetes. DN is the leading contributor to the majority of cases of end-stage renal disease (ESRD). Small extracellular vesicles (sEVs) can transport various genetic materials to recipient cells. The objective of this study was to explore how sEVs released from HK-2 cells when stimulated by high glucose levels influence renal tubular phenotypic transformation through miR-21-5p.

Methods: Both human and cell studies were utilized to explore the crosstalk between proximal renal tubules in DN. sEVs from plasma and cells were isolated using ultracentrifugation, and the differential expression of miR-21-5p in plasma sEVs from DN patients versus healthy controls was quantified using Quantitative Real-time PCR (RT-qPCR). A DN model was constructed by stimulating HK-2 cells with glucose. The expression of epithelial-mesenchymal transition (EMT) proteins in each cell group was analyzed by Western Blot (WB), while miR-21-5p levels in both cells and their sEVs were quantified using RT-qPCR. A stable transfected HK-2 cell line was constructed. The CCK8 assay, scratch assay, and WB were employed to detect EMT proteins, aiming to explore how autocrine sEVs affect tubular phenotypic transformation in diabetic nephropathy (DN).

Results: The expression of miR-21-5p in plasma sEVs was significantly elevated in the DN group compared to the healthy control group. High glucose (HG) stimulation of HK-2 cells resulted in higher miR-21-5p expression in both cells and their sEVs, leading to enhanced proliferation, migration, and EMT capacities in these cells. Co-incubation of HK-2 cells with HG-sEVs significantly enhanced the proliferation, migration, and EMT capabilities of the recipient cells, but miR-21-5p knockdown reversed these effects.

Conclusion: These results indicate that high glucose stimulates HK-2 cells to secrete sEVs, which promote DN proliferation, migration, and EMT through miR-21-5p, thereby offering new insights into the treatment of DN.

miR408 is a conserved plant miRNA family that is known to regulate genes involved in copper metabolism. However, the function of miR408 in maize leaf growth regulation under cold stress isn't defined. In this study, endogenous maize miR408 was transiently silenced by using virus-induced gene silencing (VIGS) combined with short tandem target mimic (STTM) approaches. To this end, STTM-miR408a/b was designed, synthesized, and applied to maize seedlings. Subsequently, STTM-miR408a/b (STTM) and mock-treated (M) seedlings were subjected to cold stress (C) and the growth response of the seedlings was monitored. Finally, STTM-miR408a/b-treatment successfully downregulated the expression of endogenous mir408a/b and upregulated their putative targets Basic Blue Protein (BBP) and Blue Copper Protein (BCP) antagonistically in the STTM and STTM_C groups compared to M and M_C groups. On the other hand, their putative target Laccase (LAC22) gene was upregulated in the STTM group compared to the M group, but there were no significant expression differences between the M_C and STTM_C groups. The elongation rate of the STTM-miR408a/b-treated second and third leaves was reduced by 10% and 19% resulting in 19% and 11% shortening, respectively. Furthermore, the activity of catalase (CAT) and glutathione reductase (GR) was decreased by 57% in STTM, M_C, and STTM_C, and 29% and 28% in the M_C and STTM_C groups and ascorbate peroxidase (APX) was increased by 15% in M_C and STTM_C groups, respectively. These findings illuminated the maize leaf growth response to cold via regulation of expression of miR408 and its target genes and antioxidant system.

Multidrug resistance (MDR) in Mycobacterium tuberculosis (Mtb) is a growing threat. Efflux pumps, particularly those belonging to the Major Facilitator Superfamily (MFS), play a key role in MDR. This study investigated MFS transporters across Mycobacterium spp. to understand their evolution and role in drug resistance. We conducted a proteome-wide analysis of MFS proteins in Mtb, Mycobacterium smegmatis (non-pathogenic), and Mycobacterium canettii (closely related ancestor of Mtb). Mtb, known for its MDR, possessed the highest abundance of MFS drug efflux pumps, while Mycobacterium smegmatis had the least. This suggests a link between MFS drug efflux pump abundance and MDR phenotypes. Interestingly, Mycobacterium canettii displayed an intermediate level, possibly indicating the presence of these pumps before the emergence of Mtb as a pathogen. Further analysis of Mtb proteome revealed 31 putative MFS transporters and 3 proteins from expanded MFS subfamilies. Phylogenetic analysis categorized them into thirteen distinct families based on structural features. These findings highlight the potential importance of MFS transporters in MDR and the pathogenicity of Mtb. Overall, this study highlights the evolutionary role of MFS transporters in bacterial adaptation to antibiotics. The observed correlation between efflux pump abundance and MDR suggests MFS transporters as promising targets for future anti-tuberculosis therapies. Further research on specific transporter functions within MFS subfamilies can pave the way for novel therapeutic strategies.