Mol. Genet. Genomics [JOURNAL]
Sun
200 papers
A CLN8 biallelic missense variant causes epilepsy with severe treatment-resistant psychosis.
Zulfiqar R, Kanwal A, Hameed M … +3 more , Iftikhar A, Seo GH, Naz S
Mol Genet Genomics · 2026 Jun · PMID 42377569 · Publisher ↗
Epilepsy and psychosis are dysfunctions of the nervous system that may occasionally co-occur. The current study was designed to investigate the causes of psychosis with or without epilepsy in Pakistani families. We ident...
Epilepsy and psychosis are dysfunctions of the nervous system that may occasionally co-occur. The current study was designed to investigate the causes of psychosis with or without epilepsy in Pakistani families. We identified two consanguineous families in which all affected members had treatment-resistant psychosis while three patients also had epilepsy. Every participant was examined by psychiatrists and a psychologist, while epilepsy was diagnosed by neurologists. The doctors confirmed the presence of severe psychosis with or without epilepsy in the patients and their absence in other participants. Exome sequencing identified a biallelic variant c.570G > T; p.Trp190Cys in CLN8 that segregated with the phenotype of epilepsy with psychosis in one family whereas the results for the other family were negative. CLN8 variant affects an amino acid which is conserved in diverse vertebrate orthologues. In-silico analysis indicated that substitution of tryptophan with cysteine resulted in the loss of an intramolecular interaction, which may affect protein folding. This study emphasizes that CLN8-related phenotype can include severe treatment-resistant psychosis and also provides a genotypic extension.
Expression, prognostic value and function of LMBR1L in gastric cancer.
Liang S, Zhang C, Wang C … +6 more , Liang Y, Feng X, Wang C, Jiang P, Wu S, Lu X
Mol Genet Genomics · 2026 Jun · PMID 42371227 · Publisher ↗
Gastric cancer remains a leading cause of cancer-related death worldwide, and effective prognostic biomarkers are urgently needed to guide clinical management. This study aimed to investigate the role of LMBR1L in gastri...
Gastric cancer remains a leading cause of cancer-related death worldwide, and effective prognostic biomarkers are urgently needed to guide clinical management. This study aimed to investigate the role of LMBR1L in gastric cancer. The expression of LMBR1L protein was detected by immunohistochemistry, Western blot and other methods. An LMBR1L knockdown HGC-27 cell line was constructed, and a xenograft experiment in nude mice was conducted to verify its effect on tumor growth in vivo. In addition, a nomogram model was constructed based on the expression level of LMBR1L and other clinical indicators to evaluate its predictive value for postoperative survival of gastric cancer patients. LMBR1L was highly expressed in gastric cancer. Patients with high expression of LMBR1L had lower postoperative overall survival (OS) and disease-free survival (DFS) rates than those with low expression. LASSO regression and Cox multivariate analysis showed that the expression level of LMBR1L was an independent risk factor for the prognosis of gastric cancer patients. The nomogram model constructed based on LMBR1L and other clinical indicators had a good predictive value for postoperative survival of gastric cancer patients, with areas under the ROC curve (AUC)of 0.642, 0.691 and 0.690 for 1-, 3- and 5-year survival rates, respectively. The xenograft experiment in nude mice indicated that knockdown of LMBR1L could significantly inhibit the development of gastric cancer in vivo. LMBR1L is highly expressed in gastric cancer and is closely related to poor prognosis of patients. Its regulatory effects on the biological behavior of gastric cancer in vitro and in vivo further confirm its important value as a prognostic biomarker and potential therapeutic target for gastric cancer, providing new insights into the molecular mechanisms of gastric cancer progression.
HIPK3 silencing promotes M2 macrophage polarization through NF-κB signaling pathway to enhance oral cancer progression.
Zhang R, Qiu Y, Wang W … +3 more , Chen S, Zhang L, Li C
Mol Genet Genomics · 2026 Jun · PMID 42371219 · Publisher ↗
The tumor microenvironment (TME) is crucial for the progression of oral cancer. A key feature of the TME is the dynamic plasticity of tumor-associated macrophages (TAMs), which can polarize into either pro-inflammatory M...
The tumor microenvironment (TME) is crucial for the progression of oral cancer. A key feature of the TME is the dynamic plasticity of tumor-associated macrophages (TAMs), which can polarize into either pro-inflammatory M1 or anti-inflammatory M2 phenotypes. This study aimed to investigate the role of homeodomain-interacting protein kinase 3 (HIPK3) in regulating macrophage polarization and its consequent impact on the behavior of oral squamous cell carcinoma (OSCC) cell line CAL-27. Following transfection of M0 with si-HIPK3 to downregulate HIPK3 expression, we assessed macrophage polarization markers via ELISA. Protein levels of iNOS and Arg1 were further evaluated by Western blot. We subsequently examined the effect of HIPK3-silenced macrophage polarization on the behavior of OSCC cells using functional assays. Finally, the molecular mechanism through which HIPK3 silencing regulates macrophage polarization was investigated. HIPK3 knockdown induced a significant shift from anti-tumor M1 polarization, characterized by decreased iNOS and TNF-α expression, to a tumor-promoting M2 phenotype, as evidenced by elevated levels of Arg1 and CD163. Functional assays further demonstrated that HIPK3 silencing markedly enhanced the proliferation, migration, and invasion capabilities of CAL-27 cells. Mechanistically, HIPK3 likely facilitates macrophage M2 polarization by inhibiting the NF-κB signaling pathway. In conclusion, inhibition of HIPK3 promotes M2 macrophage polarization, which in turn enhances the proliferation and migration of OSCC cells, ultimately contributing to pro-tumorigenic effects.
Comparison of microbial profiles between hospital wastewater and river water.
Gagaletsios LA, Sourenian T, Karpouzas D … +2 more , Bitar I, Papagiannitsis C
Mol Genet Genomics · 2026 Jun · PMID 42371193 · Full text
This study aimed to compare the microbial profiles between hospital wastewater and river water to assess the dissemination of clinical isolates into the environment. Two types of water samples were collected from samplin...
This study aimed to compare the microbial profiles between hospital wastewater and river water to assess the dissemination of clinical isolates into the environment. Two types of water samples were collected from sampling sites which were geographically close (wastewater from the University Hospital of Larissa and river water from the Pineios River). Gram-negative bacteria isolated from both sample types were identified using MALDI-TOF. Furthermore, the minimum inhibitory concentration (MIC) of antibiotics were evaluated. A total of 54 Gram-negative isolates, belonging to diverse species, were collected from wastewater sample and river sample. All isolates were classified as MDR, exhibiting resistance to at least one agent from more than three different antibiotic classes. Based on species identification and susceptibility profiles, 27 isolates (19 from wastewater and 8 from river-water) were selected to be further characterized by whole-genome sequencing (WGS). Analysis of WGS data, revealed the presence of different STs, even in isolates belonging to the same bacterial species. Additionally, WGS data showed that carbapenemase-encoding genes were identified in the majority of isolates. PlasmidFinder identified a huge variety of plasmid replicons among the isolates studied. In conclusion, both hospital wastewater and river water contained isolates carrying clinically relevant resistance determinants, such as carbapenemase-encoding genes. The presence of these pathogenic bacteria in the river poses a significant public health concern. Although we could not identify the origin of MDR bacteria in the river sample, these findings highlight the growing threat of antimicrobial resistance in the environment and underscore the urgent need for improved treatment methods and stricter surveillance to control its spread.
Genetic landscape of the Brahmin population of Gujarat, India, using X-chromosome STR markers.
Fulkar AA, Dave V, Kapoor K … +3 more , Sharma V, Singh A, Shukla MA
Mol Genet Genomics · 2026 Jun · PMID 42371159 · Publisher ↗
X-chromosome Short Tandem Repeats (X-STR) have been utilized in forensics and population genetics studies for more than two decades, particularly in cases involving complex kinship analysis, disaster victim identificatio...
X-chromosome Short Tandem Repeats (X-STR) have been utilized in forensics and population genetics studies for more than two decades, particularly in cases involving complex kinship analysis, disaster victim identification, sexual assault, and incest. Nevertheless, the genetic landscape of India remains underexplored using X-STR markers. In the present study, blood samples of 420 unrelated participants (133 females and 287 males) were analyzed from the Brahmin community of Gujarat, India. For the amplification of X-STR loci, the Investigator Argus X-12 QS Kit was utilized. 186 unique alleles were identified, suggesting high genetic diversity of the Brahmin population. Locus DXS10135 (PIC = 0.930) was the most polymorphic, and locus DXS7423 was the least polymorphic (PIC = 0.553). On analyzing the haplotype diversity, Linkage Group-1 (LG1) was found to have the highest haplotype diversity (0.997). Notably, LG1 was also the most informative and polymorphic linkage group (PIC = 0.994), preceded by LG4 (PIC = 0.989), LG2 (PIC = 0.988), and LG3 (PIC = 0.983). Based on the allelic and haplotype frequencies, the combined estimates for PD, PD, MEC, MEC MEC, and MEC were ≥ 0.999, demonstrating high discriminatory power of all the loci. Furthermore, inter-population phylogenetic analysis revealed high genetic affinity of Gujarat's Brahmins with other populations of the Indian subcontinent, encompassing Madhya Pradesh's Bhil tribe and Punjab's Jat Sikh. The Gujarat Brahmins also have a shorter genetic distance with other South Asian populations, including the Bangladeshi population. This research indicates that the studied X-STR markers are highly polymorphic, offering significant insights for individual identification in forensics.
RUNX2 influences alternative splicing of genes associated with gastric cancer progression by regulating SF3B6 expression in HGC-27 cells.
Han C, Liu J, Shi H … +3 more , Zhang C, Zhao Q, Song Y
Mol Genet Genomics · 2026 Jun · PMID 42371149 · Publisher ↗
Gastric cancer (GC) is a highly malignant tumor with significant morbidity and mortality rates globally. Recent studies have shown that RUNX2, a member of the RUNX family known for its role in osteoblast differentiation...
Gastric cancer (GC) is a highly malignant tumor with significant morbidity and mortality rates globally. Recent studies have shown that RUNX2, a member of the RUNX family known for its role in osteoblast differentiation and bone morphogenesis, is associated with the pathogenesis and progression of GC, while the underlying mechanisms of the pathogenesis and progression of GC are largely unknown. In this study, we investigated the role of RUNX2 in GC progression by analyzing its effects on gene expression and alternative splicing (AS) in HGC-27 cells. We silenced RUNX2 by small interfering RNA (siRUNX2), and then analyzed the globally regulated transcriptome profile by sequencing method (RNA-seq) to identify the differentially expressed genes (DEGs) and alternative splicing (AS) genes. The downstream targets of RUNX2 were identified by performing CUT&Tag and sequencing experiment in HGC-27 cells. Using RNA-seq, we identified 314 DEGs and 1120 regulated AS events (RASEs) in HGC-27 cells upon RUNX2 knockdown. The DEGs were enriched in pathways related to cell cycle regulation and apoptosis, while the RASEs were predominantly involved in cell cycle processes. These findings suggest that RUNX2 not only modulates gene expression but also extensively influences AS, which is crucial for cellular processes such as proliferation and survival. Notably, we found that RUNX2 regulates the expression of the splicing factor SF3B6 by binding to its promoter region. Our results showed that SF3B6 expression was significantly decreased in siRUNX2 samples, and its downregulation was associated with altered AS profiles of genes involved in the cell cycle. Our findings demonstrate that RUNX2 modulates the transcriptome and AS profile in GC cells, with a particular focus on its regulation of SF3B6. This study highlights the multifaceted role of RUNX2 in GC progression and suggests that targeting the RUNX2-SF3B6 axis could be a promising therapeutic strategy for GC.
Retraction Note: Transcriptional characterization of sepsis in a LPS porcine model.
Neill R
Mol Genet Genomics · 2026 Jun · PMID 42370960 · Publisher ↗
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Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.
Petrin AL, Machado-Paula LA, Keen HL … +10 more , Hovey L, Doolittle B, Dunlay L, Awotoye W, Xie XJ, Zeng E, Butali A, Marazita ML, Murray JC, Moreno-Uribe LM
Mol Genet Genomics · 2026 Jun · PMID 42334621 · Full text
Understanding how genetic variants influence disease risk through molecular mechanisms remains a central challenge in complex disease genetics. Nonsyndromic orofacial clefts (OFCs) exemplify this challenge, with most ris...
Understanding how genetic variants influence disease risk through molecular mechanisms remains a central challenge in complex disease genetics. Nonsyndromic orofacial clefts (OFCs) exemplify this challenge, with most risk loci residing in non-coding regions. We hypothesized that common genetic variants influence OFC risk by modulating DNA methylation at regulatory elements through methylation quantitative trait loci (meQTLs). We analyzed 10 OFC-associated SNPs against genome-wide DNA methylation profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. Findings were validated using 358 cleft-discordant sibling pairs with MethyLight assays. We performed formal mediation analysis, genotype-tissue interaction and cross-referenced with the mQTL Database to assess developmental timing. Nine meQTLs were validated, including rs987525 (8q24)-cg16561172 (MYC) (P = 9.6 × 10⁻⁶), which mapped to a mesendoderm-active enhancer upstream of MYC. Genotype × tissue interaction confirmed tissue-specificity (P = 1.00 × 10), with stronger effects in oral-derived tissue (saliva). Additional validated SNP-CpG associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4. While effect sizes correlated between tissues (r = 0.81), formal mediation analysis indicated individual CpG sites do not fully mediate SNP-phenotype relationships, suggesting coordinated epigenetic mechanisms. Most associations showed peak effects during childhood, while 8q24 showed unique adult-specific patterns. We identified genetic variants influencing methylation at craniofacial regulatory elements, and provided a mechanistic link for a major risk locus, 8q24, with tissue-specific effects in saliva. While individual CpG sites did not fully mediate the genetic risk, our findings identified specific regulatory regions where coordinated epigenetic changes may contribute to OFC susceptibility.
Genotype-dependent metabolic and inflammatory regulation at the ANRIL locus in human primary macrophages.
Kirsan-Kesici CB, Ozuynuk-Ertugrul AS, Komurcu-Bayrak E … +1 more , Coban N
Mol Genet Genomics · 2026 Jun · PMID 42319513 · Publisher ↗
The long non-coding RNA ANRIL and several single-nucleotide polymorphisms have been strongly implicated in genetic susceptibility to coronary artery disease (CAD). However, how these variants influence gene expression re...
The long non-coding RNA ANRIL and several single-nucleotide polymorphisms have been strongly implicated in genetic susceptibility to coronary artery disease (CAD). However, how these variants influence gene expression remains incompletely understood. This study aims to investigate genotype-dependent differences in linear and circular ANRIL isoform expression and selected CAD- and diabetes-related genes in monocyte-derived macrophages from healthy adult males carrying rs1333049, rs10757274, and rs564398 variants. Peripheral blood monocytes from healthy male donors with specific ANRIL genotypes were isolated and differentiated into macrophages using macrophage colony-stimulating factor. Monocyte identity and macrophage differentiation were confirmed by flow cytometry and confocal imaging. Gene expression levels of CDKN2A, CDKN2B, ABCA1, PRKAA1, PPARGC1A, TNFA, TNFAIP3, and circular and linear ANRIL transcripts were quantified by qRT-PCR. Expression differences across genotype groups and genotype-dependent correlations were assessed. The rs10757274/rs1333049 AA/CC genotype was associated with reduced expression of PPARGC1A and ABCA1, accompanied by lower TNFA and higher TNFAIP3 expression. In contrast, carriage of the G allele at rs10757274/rs1333049 was associated with increased expression of CDKN2A and linear ANRIL. The rs564398 CC genotype was associated with reduced PPARGC1A expression and altered PRKAA1 levels. Correlation analyses revealed genotype-specific associations between ANRIL isoforms and selected genes. These findings suggest that ANRIL variants are associated with genotype-dependent differences in macrophage gene expression across pathways of cell cycle regulation, inflammation, lipid metabolism, and energy homeostasis. Although exploratory, the results support the possibility that CAD- and diabetes-associated 9p21.3 variants may partly exert their effects through such transcriptional alterations.
Single-cell transcriptomics identifies key immune-suppressive cells and their driver genes in the bladder cancer microenvironment with prognostic implications.
Song W, Han G, Li Z … +2 more , Hu J, Ma K
Mol Genet Genomics · 2026 Jun · PMID 42319469 · Publisher ↗
The immunosuppressive tumor microenvironment (TME) serves as a central driver of bladder cancer (BCa) progression and prognosis. While its significance is widely acknowledged, the key cellular subsets that mediate this i...
The immunosuppressive tumor microenvironment (TME) serves as a central driver of bladder cancer (BCa) progression and prognosis. While its significance is widely acknowledged, the key cellular subsets that mediate this immunosuppressive state and their core regulatory genes remain incompletely understood. Key immunosuppressive cellular subsets and their signature genes were systematically identified using single-cell RNA sequencing (scRNA-seq) data from BCa samples. A prognostic risk model was then constructed via univariate and multivariate Cox regression analyses, based on bulk RNA-seq datasets and the identified signature genes. The role of SUSD2 was further validated in vitro using qRT-PCR, Western blot, immunofluorescence, proliferation, and invasion assays. Compared with adjacent normal tissues, BCa tissues showed significant enrichment of stromal cells (e.g., epithelial cells, fibroblasts). Among these stromal populations, the proportion of myofibroblast-like cancer-associated fibroblasts (myCAFs) was significantly increased in BCa tissues, and high myCAF infiltration was closely associated with poor patient prognosis. Pseudotime trajectory analysis confirmed that fibroblast differentiation in BCa shifts toward a terminal state (State 3), which is predominantly composed of myCAFs. A prognostic model established using myCAF-related signature genes (TMEM74B, ABCC9, FCMR, ALG9, SUSD2, and ETV7) exhibited stable predictive performance in both training and validation cohorts, with SUSD2 identified as a risk-related gene. In vitro experiments revealed that SUSD2 knockdown inhibited myCAF activation and extracellular matrix secretion, thereby attenuating its promotional effects on BCa cell proliferation and invasion. The TGF-β receptor inhibitor SB-431542could reverse the facilitative effects of SUSD2 overexpression on tumor cell proliferation and migration. Our findings identify myCAFs as a core regulatory cellular subset and SUSD2 as a key molecule within the immunosuppressive TME of BCa. Additionally, SUSD2 may trigger the activation of the TGF-β/Smad signaling cascade to induce myCAF activation, thereby accelerating BCa progression. These results provide novel potential targets and a theoretical basis for prognosis assessment and TME-targeted therapy in BCa.
DDX39B drives the m6A modification of LDHA to promote trophoblast proliferation.
Li C, Zhou W, Shen Y … +3 more , Zhang J, Jiang Y, Li R
Mol Genet Genomics · 2026 Jun · PMID 42319456 · Publisher ↗
Preeclampsia (PE), a hypertensive disorder unique to pregnancy, is linked to impaired trophoblast function. DEAD-box helicase 39B (DDX39B) plays key roles in embryonic development. This study investigated its role in reg...
Preeclampsia (PE), a hypertensive disorder unique to pregnancy, is linked to impaired trophoblast function. DEAD-box helicase 39B (DDX39B) plays key roles in embryonic development. This study investigated its role in regulating trophoblast biology during PE progression. We conducted functional assays using CCK-8, clone formation, EdU, Transwell, Wound healing and TUNEL in the HTR-8/SVneo trophoblast cells. The interaction between Wilms tumor 1-associating protein (WTAP) and DDX39B was analyzed by Co-IP assay. RIP assay or RNA pull down were used to assess the association between the ELAV-like RNA-binding protein 1 (ELAVL1)/WTAP and L-lactate dehydrogenase A (LDHA) mRNA. Additionally, MeRIP assay was employed to evaluate m6A levels on LDHA transcripts. Overexpression of DDX39B promoted the proliferation and migration of trophoblast cells and suppressed cells apoptosis, while DDX39B knockdown had the opposite result. In addition, WTAP knockdown reversed the promoting effects of DDX39B overexpression on trophoblast proliferation and migration. Mechanistically, DDX39B promoted post-translational stabilization of WTAP by directly interacting with WTAP protein. WTAP enhanced the m6A methylation of LDHA mRNA by recruiting ELAVL1. As expected, LDHA knockdown abrogated the pro-proliferative and anti-apoptotic effects of WTAP overexpression on trophoblasts. Our findings established a novel DDX39B/WTAP/m6A/LDHA regulatory axis, wherein DDX39B acted as an RNA-binding protein to stabilize WTAP, enhancing LDHA expression and promoting trophoblast proliferation, migration, and survival. Dysregulation of this pathway might contribute to PE pathogenesis, offering new avenues for targeted therapies.
Unveiling the role of heat shock protein 83 (HSP83) in Gossypium hirsutum in enhancing whitefly stress tolerance.
Sajjad MW, Naqvi RZ, Imran I … +3 more , Yasin MA, Akhtar M, Amin I
Mol Genet Genomics · 2026 Jun · PMID 42301517 · Publisher ↗
Heat shock proteins (HSPs) are key molecular chaperones that control protein homeostasis and stress signalling in plants. They have been widely studied for abiotic stresses, such as drought and heat; however, their role...
Heat shock proteins (HSPs) are key molecular chaperones that control protein homeostasis and stress signalling in plants. They have been widely studied for abiotic stresses, such as drought and heat; however, their role in insect-mediated biotic stress is little known, especially in polyploid crops like cotton, which is an important economic crop. Whitefly, Bemisia tabaci (Gennadius), infestation is a serious agronomic constraint in cotton (Gossypium spp.); however, efforts to completely investigate the genetic and molecular components driving host resistance against this pest have not been entirely successful yet. In this study, a genome-wide analysis of heat shock proteins (HSPs) families in cotton varieties has been conducted to investigate the involvement of HSPs in whitefly stress. About 505 HSPs genes are found unequally distributed in the genomes of four cotton species. Chromosomal locations and their mapping have shown the highest number of genes at chromosome 9 in G. hirsutum and G. barbadense; at chromosome 6 in G. raimondii; and at chromosome 5 in G. arboreum. Gene ontology, evolutionary dynamics and domain analysis have been performed for HSP families in cotton, which showed the presence of different conserved domains important for biological as well as molecular functions. The HSP83, belonging to the HSP90 gene family, has been focused on in cotton species for this particular aspect due to the differential expression suggested by reference RNA-sequencing data. The gene structure of these HSP83s is similar, and all contain a conserved HSP90 superfamily coding for important domains like HSP90-like ATPase. In addition, various important cis-regulatory elements like bZIP, WRKY, and GT1-motif, related to different signalling and stress patterns during the central dogma, have been found in the promoter regions of HSP83s. The functional validation was done by virus-induced gene silencing (VIGS) of the target HSP83 gene found at chromosome 12 in G. hirsutum which showed increased whitefly infestation in the infiltrated plants. These results demonstrate that HSP83 is a conserved molecular regulator of cotton's resistance to whiteflies and that it aids in maintaining stress-responsive signalling networks when insects attack. HSP83's evolutionary conservation, promoter architecture, and functional validation all point to it being an important component of polyploid cotton's defensive mechanism. These results provide a molecular foundation for integrating chaperone-mediated stress regulation into crop development initiatives and further our knowledge of HSP90-family proteins in plant-insect interactions.
GOLPH3 promotes papillary thyroid carcinoma by regulating the TGF-β signaling pathway.
Peng H, Zhou Y, Li F … +4 more , Xia S, Lin L, Xu Y, Chen Q
Mol Genet Genomics · 2026 Jun · PMID 42301509 · Publisher ↗
Thyroid cancer incidence is rising globally, with papillary thyroid carcinoma (PTC) being the most common subtype. While most patients have favorable outcomes, a subset develops aggressive, therapy-resistant disease, hig...
Thyroid cancer incidence is rising globally, with papillary thyroid carcinoma (PTC) being the most common subtype. While most patients have favorable outcomes, a subset develops aggressive, therapy-resistant disease, highlighting an urgent need to understand the molecular drivers of PTC progression. Golgi phosphoprotein 3 (GOLPH3) has emerged as a potential oncogene in multiple solid tumors, yet its functional role and mechanistic basis in PTC remain poorly defined. This study aims to elucidate the biological function of GOLPH3 in PTC progression and investigate whether it exerts oncogenic effects through the TGF-β signaling pathway. qPCR and WB were utilized to determine the expression of GOLPH3 in PTC cells. The KEGG analysis was used to identify the signaling pathways enriched by GOLPH3. CCK-8, flow cytometry, and Transwell assays were respectively utilized to examine the viability, apoptosis level, as well as PTC cells' migration and invasion abilities. The proportion of senescent cells was analyzed through β-galactosidase staining. WB was applied to detect the expression of TGF-β signaling pathway markers (TGF-β1, SMAD2, p-SMAD2, p-SMAD3, SMAD3) as well as EMT markers (E-cadherin, N-cadherin, Snail). GOLPH3 expression was upregulated in PTC cells. GOLPH3 knockdown mitigated the viability, invasiveness, and motility of cancer cells and elevated the apoptosis rate and the proportion of senescent cells. KEGG analysis demonstrated that GOLPH3 was significantly enriched in the TGF-β signaling pathway, and that GOLPH3 knockdown could inhibit the TGF-β pathway and block the EMT process. Additionally, via activating this pathway, GOLPH3 overexpression promoted PTC progression. However, as an inhibitor of this pathway, LY2109761 could reverse the effects induced by GOLPH3 overexpression. Collectively, these findings establish GOLPH3 as a critical driver of PTC malignancy through TGF-β pathway activation, providing a mechanistic link between Golgi function and cancer signaling. This work not only advances our understanding of PTC pathogenesis but also identifies GOLPH3 as a potential therapeutic target for aggressive PTC, offering a paradigm for exploring Golgi-associated proteins in endocrine malignancies.
miR-133b induces antitumor immunity in cervical cancer through modulating CMTM6/PD-L1 axis.
Tan WM, Wang JQ, Li L … +3 more , Liu XJ, Wang HB, Zeng H
Mol Genet Genomics · 2026 Jun · PMID 42301387 · Publisher ↗
Immune evasion mediated by the PD-L1 pathway remains a major hurdle in the effective treatment of cervical cancer (CC). While microRNAs (miRNAs) are known to critically regulate host immune responses, their specific role...
Immune evasion mediated by the PD-L1 pathway remains a major hurdle in the effective treatment of cervical cancer (CC). While microRNAs (miRNAs) are known to critically regulate host immune responses, their specific roles in modulating the immunosuppressive microenvironment in CC remain largely elusive. Therefore, this study aims to elucidate the scope, clinical relevance, and mechanistic actions of the novel miR-133b/CMTM6/PD-L1 axis in cervical cancer immune evasion. Through a comprehensive series of in vitro and in vivo assays, we evaluated the expression and function of miR-133b, CMTM6, and PD-L1 in CC tissues and cell lines. Our results revealed that miR-133b is significantly downregulated in CC, which strongly correlates with poor patient prognosis. Mechanistically, miR-133b directly targets CMTM6, thereby suppressing PD-L1 expression. In clinical CC tissues, miR-133b levels were negatively correlated with both CMTM6 and PD-L1. Utilizing an immune-competent murine syngeneic model, we demonstrated that miR-133b overexpression profoundly inhibited tumor growth. This tumor suppression was accompanied by enhanced intra-tumoral infiltration of CD4 and CD8T cells and an attenuated presence of myeloid-derived suppressor cells (MDSCs). Furthermore, co-culture experiments revealed that miR-133b-overexpressing CC cells significantly increased IFN-γ release, decreased IL-10 secretion, and attenuated T cell apoptosis effects that were mechanistically dependent on the inhibition of the CMTM6/PD-L1 axis. In conclusion, our findings establish miR-133b as a critical tumor suppressor and immune modulator in cervical cancer. By deciphering the miR-133b/CMTM6/PD-L1 regulatory network, this work provides a novel mechanistic perspective on CC immune evasion, suggesting that targeting this axis holds significant promise as a therapeutic strategy to reverse the immunosuppressive microenvironment and enhance anti-tumor immunity.
Genomic and molecular dynamics analysis of mefA-encoded macrolide efflux protein from Tn2009 and Tn2010 in Streptococcus pneumoniae.
Maladan Y, Retnaningrum E, Daryono BS … +2 more , Sari RF, Safari D
Mol Genet Genomics · 2026 Jun · PMID 42298186 · Publisher ↗
Antibiotic resistance in Streptococcus pneumoniae remains a major clinical challenge, particularly for macrolides such as erythromycin. This resistance is commonly associated with transposons Tn2009 and Tn2010 carrying t...
Antibiotic resistance in Streptococcus pneumoniae remains a major clinical challenge, particularly for macrolides such as erythromycin. This resistance is commonly associated with transposons Tn2009 and Tn2010 carrying the mefA gene, which encodes a macrolide efflux protein. This study investigated the genetic characteristics of mefA from Indonesian clinical isolates and elucidated its efflux mechanism using integrated genomic analysis and molecular dynamics simulations. Whole-genome sequencing confirmed the presence of Tn2009 and Tn2010 in clinical isolates. Multiple sequence alignment showed high conservation of mefA (98-100% identity), indicating strong evolutionary stability within the species. A homology model of the mefA encoded efflux protein was constructed and used for molecular docking, revealing stable erythromycin binding within the efflux channel with multiple favorable binding poses. Molecular dynamics simulations (200 ns) demonstrated structural stability of the protein, with an average root mean square deviation of 0.174 nm. Root mean square fluctuation analysis identified localized flexibility in residues Asn195-Ser199, suggesting a functionally relevant intracellular loop involved in conformational dynamics. Despite stable interactions, erythromycin remained confined within a localized channel region and did not undergo spontaneous translocation under equilibrium conditions. Steered molecular dynamics simulations indicated that ligand transport requires external force to overcome an initial energetic barrier of 553.07 kJ/mol/nm, followed by stepwise displacement through multiple transient binding sites, consistent with a multi-site relay mechanism. Umbrella sampling further revealed a rugged free energy landscape, with a maximum potential of mean force (PMF) of ~ 45 kcal/mol near the channel exit region. The PMF profile, reconstructed using WHAM across ~ 30 windows, showed well-converged overlap and multiple intermediate minima, indicating a stable sampling of the reaction coordinate. Collectively, these findings provide structural and energetic insights into mefA mediated erythromycin resistance in S. pneumoniae. The results support a mechanism involving stable substrate binding, localized conformational flexibility, and substantial energy barriers requiring active transport, highlighting potential targets for efflux inhibition strategies.
Integrated multi-technology exploration of the mechanism by which Badushengji San regulates core targets in diabetic foot ulcer.
Cai Y, Lin A, Shen J … +4 more , Zhang X, Zhou J, Rang Y, Chen X
Mol Genet Genomics · 2026 Jun · PMID 42298176 · Publisher ↗
Diabetic Foot Ulcer (DFU), a prevalent and refractory diabetic complication, lacks clear pathological targets and effective therapeutic strategies. This study aimed to identify potential DFU biomarkers and preliminarily...
Diabetic Foot Ulcer (DFU), a prevalent and refractory diabetic complication, lacks clear pathological targets and effective therapeutic strategies. This study aimed to identify potential DFU biomarkers and preliminarily explore the mechanism of Badushengji San (BDS) in treating DFU. Transcriptome datasets (GSE199939, GSE134431) and single-cell RNA sequencing (scRNA-seq) data (GSE165816) were retrieved to screen differentially expressed genes (DEGs) and DFU-related cell subsets. Intersection genes among DEGs, drug targets, and high-dimensional Weighted Gene Co-Expression Network Analysis (hdWGCNA) genes were then identified. Core biomarkers were subsequently screened using Least Absolute Shrinkage and Selection Operator (LASSO), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Boruta algorithms. Macrophages were defined as DFU-associated core cells. Three biomarkers (CYCS, HMOX1, UPP1) showed diagnostic value (the area under the curve (AUC) of UPP1 = 0.973). BDS (50 ng/mL) reversed 40 mM glucose-induced L929 cell injury by restoring HMOX1 and suppressing UPP1 expression. These biomarkers were enriched in pathways like nuclear factor-kappa B (NF-κB), and their abnormal expression was closely linked to DFU pathological progression. Notably, Benzoyl paeoniflorin had the lowest binding energy (-10.06 kcal/mol) with UPP1. Collectively, this study identified CYCS, HMOX1, and UPP1 as potential biomarkers for DFU and preliminarily revealed the potential regulatory effect and molecular characteristics of BDS in DFU intervention, which lays a bioinformatic foundation and provides preliminary experimental clues for further in vivo mechanism research.
Identification and functional characterization of a novel pathogenic DVL1 gene variant in Robinow syndrome.
Kumar A, Rai S, Kumar A … +3 more , Dey C, Chakraborty S, Munshi A
Mol Genet Genomics · 2026 Jun · PMID 42298173 · Publisher ↗
Robinow syndrome is a rare genetic disorder characterized by distinct craniofacial dysmorphism, mesomelic limb shortening and genital hypoplasia. The disorder has been reported to be inherited in an autosomal dominant as...
Robinow syndrome is a rare genetic disorder characterized by distinct craniofacial dysmorphism, mesomelic limb shortening and genital hypoplasia. The disorder has been reported to be inherited in an autosomal dominant as well as recessive patterns with a prevalence of 1:500000. In this study, we aimed to identify the genetic basis and structural consequences of disease in a clinically diagnosed case. A 3-months old male child from the Southwest Punjab region of India, born out of a consanguineous marriage, was presented with features including hypertelorism, midface hypoplasia, short stature, brachydactyly and genital anomalies. Whole-exome sequencing revealed a novel heterozygous pathogenic frameshift mutation, c.1644del (p.F549Sfs*125) in exon 14 of the DVL1 gene. This variant was absent in significant population databases and was therefore classified as pathogenic based on ACMG criteria. Familial segregation analysis by Sanger sequencing indicated it to be a de novo mutation since it was not observed in the parents as well as the elder male sibling. Further, comparative molecular dynamics analyses reveal that the mutation profoundly destabilizes DVL1, as the wild-type protein maintains stable Root Mean Square Deviation (RMSD), moderate flexibility, compact folding, and controlled essential motions, consistent with a properly folded, functional state. In contrast, the mutant displays persistent structural instability, excessive flexibility, loss of compactness, disrupted hydrogen-bond networks, and exaggerated collective motions, collectively indicating loss of stable dynamic features required for normal DVL1 function and likely non-functionality. In conclusion, this study reports a novel pathogenic variant in DVL1 associated with Robinow syndrome in this geographical region and highlights the importance of integrating genomic and structural analyses to understand disease mechanisms. These findings expand the mutational spectrum and have important implications for precise diagnosis, genetic counselling, and future studies on targeted molecular mechanisms.
A modality-aware CRISPR actionability framework for functional prioritization of genome-wide significant type 2 diabetes loci.
Uddin MM, Khan SMZA
Mol Genet Genomics · 2026 Jun · PMID 42298143 · Publisher ↗
Genome-wide association studies (GWAS) have identified numerous loci associated with Type 2 Diabetes (T2D), yet translating statistical signals into experimentally testable hypotheses remains a central challenge in post-...
Genome-wide association studies (GWAS) have identified numerous loci associated with Type 2 Diabetes (T2D), yet translating statistical signals into experimentally testable hypotheses remains a central challenge in post-GWAS biology. The predominance of non-coding regulatory variants complicates target gene assignment and raises uncertainty regarding optimal clustered regularly interspaced short palindromic repeats (CRISPR) perturbation strategy. Here, we present a structured CRISPR Actionability Framework that integrates genomic context, pancreatic islet enhancer overlap, tissue-specific expression validation, and locus clarity into a quantitative CRISPR Actionability Score (CAS). We applied this framework to ten genome-wide significant T2D loci and assigned modality-aware CRISPR strategies (knockout versus CRISPR interference). CAS values ranged from 4 to 10, enabling tiered prioritization into high, moderate, and lower experimental priority classes. High-priority loci included SLC30A8, TCF7L2, and KCNJ11, which demonstrated strong regulatory or coding evidence combined with islet expression support. By explicitly linking genomic architecture to perturbation modality, this framework provides a transparent and reproducible bridge between statistical genetics and functional genome editing. This approach establishes a scalable template for rational CRISPR target selection in complex disease research.
Unravelling genetic diversity in grain amaranth (Amaranthus hypochondriacus L.) core accessions using genome-wide SNP markers.
Boro J, Yadav HK
Mol Genet Genomics · 2026 Jun · PMID 42298028 · Publisher ↗
Grain amaranth (Amaranthus hypochondriacus L.) is a gluten-free pseudocereal with high nutritional value and notable climate resilience; however, its genome-wide population structure and genetic diversity remain poorly c...
Grain amaranth (Amaranthus hypochondriacus L.) is a gluten-free pseudocereal with high nutritional value and notable climate resilience; however, its genome-wide population structure and genetic diversity remain poorly characterized. Given the considerable diversity observed in its gene pool, comprehensive genome-scale characterization are required to understand the genetics of important traits for effective breeding and improvement. Here, we employed Whole-Genome Sequencing (WGS) approach to generate genome-wide SNPs in a core accessions of A. hypochondriacus, leveraging the available reference genome. A total of 248 accessions, comprising Indian and some exotic accessions, were sequenced through Illumina paired-end sequencing, yielding 285,236 high-quality SNPs, with an average of ~ 20 × genome coverage. Population structure analysis identified six sub-populations among the core accessions, consistent with kinship and phylogenetic analyses, reflecting substantial genetic diversity within the genetic material used. Linkage disequilibrium (LD) analysis indicated moderate genome-wide LD, with an average decay distance of 29.8 kb, although strong LD (r ≥ 0.8) was observed in some marker pairs. Functional annotation of 17,350 SNP-associated genes revealed enrichment of loci related to metabolic processes, stress responses, and developmental pathways, providing biological context observed genomic variation. Further, several genetically diverse accessions identified in this study offer valuable resources for future breeding efforts. Together, these results establish a robust genomic framework for A. hypochondriacus that supports future genome-wide association studies and genetic improvement efforts in grain amaranth.
WTAP-mediated mA methylation of CEP55 promotes immune evasion in lung adenocarcinoma by activating the PI3K/AKT/mTOR pathway.
Yang T, Chen T, Yang R
Mol Genet Genomics · 2026 Jun · PMID 42298019 · Publisher ↗
Lung adenocarcinoma (LUAD) is the most lethal subtype of lung cancer, and its occurrence and progression are closely correlated with immune escape. CEP55 is upregulated in a variety of malignancies and participates in tu...
Lung adenocarcinoma (LUAD) is the most lethal subtype of lung cancer, and its occurrence and progression are closely correlated with immune escape. CEP55 is upregulated in a variety of malignancies and participates in tumor progression, yet its specific role in the immune regulation of LUAD remains poorly defined. Due to the unclear mechanism of immune escape, the therapeutic efficacy of immunotherapy for LUAD is still unsatisfactory. Therefore, it is essential to further elucidate the underlying molecular mechanisms and identify novel therapeutic targets. This study aims to explore the biological function of CEP55 in LUAD immune escape, as well as to clarify its upstream regulatory mechanism and downstream signaling pathways. CEP55 expression in LUAD tissues was assessed utilizing data from TCGA-LUAD and validated in cells. Bioinformatics approaches were employed to explore CEP55-enriched signaling pathways and their link to CD8⁺ T cell infiltration. A CD8⁺ T-tumor cell co-cultured model was established, and LDH release, ELISA, and CFSE staining were utilized to assess CD8⁺ T cell cytotoxicity and proliferation. To uncover the role of CEP55 in LUAD cell behavior, we employed CCK-8, EdU labeling, Transwell assays, and flow cytometry to systematically evaluate its effects on proliferation, migration, invasion, and apoptosis. Western blotting was performed to measure key signaling pathway proteins expression level. Potential upstream regulators of CEP55 mA modification were identified through database mining, followed by validation using RIP, MeRIP-qPCR, and WB. CEP55 was highly expressed in LUAD and inversely associated with CD8⁺ T cell infiltration. Knockdown of CEP55 in LUAD enhanced tumor-killing activity of CD8⁺ T cells in a co-culture system and significantly suppressed LUAD cell proliferation, migration, invasion, and anti-apoptotic capacity. CEP55 was positively correlated with WTAP in LUAD. WTAP stabilized CEP55 mRNA expression via mA modification, while CEP55 activated the PI3K/AKT/mTOR pathway, upregulating PD-L1. This led to CD8⁺ T cell exhaustion and promoted tumor immune evasion. This study reveals a critical mechanism whereby WTAP upregulates CEP55 expression via m⁶A modification, thereby activating the PI3K/AKT/mTOR signaling pathway, inhibiting the anti-tumor activity of CD8⁺ T cells, and ultimately facilitating LUAD progression. These findings indicate that CEP55 serves as a promising therapeutic target for LUAD immunotherapy, providing novel theoretical evidence to improve the efficacy of immune treatment.
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