Search Results (67)

Background and Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that belong to genetic and epigenetic mechanism. Despite the recent advantages in next-generation sequencing (NGS) technology, ASD etiology is still unclear. Materials and Methods: In this study, we tested a customized target genetic panel consisting of 74 genes in a cohort of 53 ASD individuals. The tested panel was designed from the SFARI database. Results: Among 53 patients analyzed using a targeted genetic panel, 102 rare variants were identified, with nine individuals carrying likely pathogenic or pathogenic variants considered genetically “positive.” We identified six de novo variants across five genes (POGZ 2 variants, NCOR1, CHD2, ADNP, and GRIN2B), including two variants of uncertain significance in POGZ p.Thr451Met and NCOR1 p.Glu1137Lys, one likely pathogenic variant in GRIN2B p.Leu714Gln, and three pathogenic variants in POGZ p.Leu775Valfs32, CHD2 p.Thr1108Metfs8, and ADNP p.Pro5Argfs*2. Conclusions: This study presents a comprehensive characterization of the targeted gene panel used for genetic analysis, while critically evaluating its diagnostic limitations within the context of contemporary genomic approaches. A pivotal accomplishment of this study was the ClinVar submission of novel de novo variants which expands the documented mutational spectrum of ASD-associated genes and enhances future diagnostic interpretation. Full article

BQ323636.1 (BQ), a splice variant of NCOR2, is associated with endocrine therapy resistance and poorer prognosis in ER-positive breast cancer. This study investigates the role of BQ in modulating lipid metabolism to support tumor growth. RNA sequencing of BQ-overexpressing breast cancer cells revealed significant enrichment of fatty acid metabolism pathways (hsa01212 and hsa00061; p < 0.05), with ACSL4 identified as a key target. We show that BQ disrupts the NCOR2-PPARγ interaction, leading to ACSL4 upregulation, which enhances fatty acid oxidation (FAO), acetyl-CoA by 1.8-fold, and ATP production by 2.5-fold to fuel tumor proliferation. BQ also upregulates FASN and SCD, increasing lipids. A metabolites study with mass spectrometry indicated that BQ overexpression increases the fatty acid amount from 47.97 nmol/10⁶ cells to 75.18 nmol/10⁶ cells in MCF7 and from 56.19 nmol/10⁶ cells to 95.37 nmol/10⁶ cells in ZR-75. BQ activates NRF2, which mitigates ROS-induced stress, promoting cell survival. Targeting ACSL4 with the inhibitor PRGL493 reduced ATP production and suppressed tumor growth in vitro and in vivo, without inducing apoptosis, suggesting a cytostatic effect. PRGL493 treatment can reduce BQ overexpressing tumors by 40% in the xenograft model. These results highlight BQ can serve as a transcriptional hub driving lipid metabolism via ACSL4 in breast cancer. Our findings suggest that ACSL4 inhibition could be a novel therapeutic strategy to overcome treatment resistance in high-BQ expressing ER-positive breast cancer. Full article

Peroxisome proliferator-activated receptors (PPARs), composed of the α/δ/γ subtypes, are ligand-activated nuclear receptors/transcription factors that sense endogenous fatty acids or therapeutic drugs to regulate lipid/glucose metabolism and oxidative stress. PPAR forms a multiprotein complex with a retinoid X receptor and corepressor complex in an unliganded/inactive state, and ligand binding induces the replacement of the corepressor complex with the coactivator complex to initiate the transcription of various genes, including the metabolic and antioxidant ones. We investigated the processes by which the corepressor is replaced with the coactivator or in which two coactivators compete for the PPARα/δ/γ-ligand-binding domains (LBDs) using single- and dual-emission fluorescence resonance energy transfer (FRET) assays. Single-FRET revealed that the respective PPARα/δ/γ-selective agonists (pemafibrate, seladelpar, and pioglitazone) induced the dissociation of the two corepressor peptides, NCoR1 and NCoR2, from the PPARα/δ/γ-LBDs and the recruitment of the two coactivator peptides, CBP and TRAP220. Meanwhile, dual-FRET demonstrated that these processes are simultaneous and that the four coactivator peptides, CBP, TRAP220, PGC1α, and SRC1, were competitively recruited to the PPARα/δ/γ-LBDs with different preferences upon ligand activation. Furthermore, the five newly obtained cocrystal structures using X-ray diffraction, PPARα-LBDs–NCoR2/CBP/TRAP220/PGC1α and PPARγ-LBD–NCoR2, were co-analyzed with those from our previous studies. This illustrates that these coactivators bound to the same PPARα-LBD loci via their consensus LXXLL motifs in the liganded state; that NCoR1/NCoR2 corepressors bound to the same loci via the IXXXL sequences within their consensus LXXXIXXXL motifs in the unliganded state; and that ligand activation induced AF-2 helix 12 formation that interfered with corepressor binding and created a binding space for the coactivator. These PPARα/γ-related biochemical and physicochemical findings highlight the coregulator dynamics on limited PPARα/δ/γ-LBDs loci. Full article

This study aimed to evaluate the influence of back-fat thickness (BF), at mating of sows, on autophagy in placenta and the potential mechanism. The sows were divided into two groups according to their BF at mating: BFI (15–20 mm, n = 14) and BFII (21–27 mm, n = 14) as the maternal obesity group. The placental samples used for investigating autophagic function and fatty acid profiles were obtained by vaginal delivery. Our results demonstrated that autophagy defects were observed in placenta from BFII sows along with altered circulating and placental fatty acid profiles. Indicative of impaired autophagy, reduced autophagic vesicles as well as LC3-positive puncta were linked to decreased mRNA or protein expression of autophagy-related genes, including ATG5, ATG7, Beclin1, ATG12, LC3, LAMP1 and LAMP2 in the placenta of BFII sows (p < 0.05). Meanwhile, we found reduced conversion of LC3-I to LC3-II and up-regulated protein content of p62 in the placenta from BFII group (p < 0.05). Furthermore, excessive back-fat was also associated with increased activation of AKT/mTOR signaling and decreased mRNA content of transcription factors regulating the autophagic pathway, including PPARα and PGC1α, but increased mRNA expression of NcoR1 in placenta. Together, these findings indicate that maternal obesity incites autophagy injury in pig term placenta, which may contribute to augmented placental lipid accumulation and therefore impaired placental function. Full article

Understanding the genetic characteristics of indigenous goat breeds is vital for their conservation and breeding. Haimen goats, native to China’s Yangtze River Delta, possess distinctive traits such as white hair, moderate growth rate, high-quality meat, and small body size. However, knowledge regarding the genetic structure and germplasm characteristics of Haimen goats remains limited. In this study, we performed 20× whole-genome resequencing of 90 goats (60 Haimen goats and 30 Boer goats) to identify single-nucleotide polymorphisms (SNPs) and insertions/deletions (Indels) associated with growth traits. Here, we analyzed population genetic structure and genome-wide selection signatures between the Haimen and Boer goats based on whole-genome resequencing data. The principal component analysis (PCA) and neighbor-joining (N-J) tree results demonstrated significant genetic differentiation between the Haimen and Boer goats. The nucleotide diversity (Pi) and linkage disequilibrium (LD) decay results indicated higher genomic diversity in the Haimen goat population. Furthermore, selective sweep analysis identified candidate genes associated with growth traits. These genes exhibited strong selection signatures and were related to body size (DONSON, BMPR1B, and EPHA5), muscle development (GART, VGLL3, MYH15), and fat metabolism (ADAMTS5, LRP6, XDH, CPT1A, and GPD1). We also identified growth-related candidate genes (NCOR1, DPP6, NOTCH2, and FGGY) specific to Haimen goats. Among these genes, pancreatic lipase-related protein 1 (PNLIPRP1) emerged as the primary candidate gene influencing growth phenotypes. Further analysis revealed that a 26 bp Indel in PNLIPRP1 increased its gene expression, suggesting that this Indel could serve as a molecular marker for early marker-assisted selection, potentially enhancing early growth in goats. These findings provide valuable molecular markers and candidate genes for improving growth traits in Haimen goat breeding. Full article

Mutations in the genes ANKRD26, RUNX1, and ETV6 cause three clinically overlapping thrombocytopenias characterized by a predisposition to hematological neoplasms. The ANKRD26 gene, which encodes a protein involved in protein-protein interactions, is downregulated by RUNX1 during megakaryopoiesis. Mutations in 5′UTR of ANKRD26, leading to ANKRD26-RT, disrupt this regulation, resulting in the persistent expression of ANKRD26, which leads to impaired platelet biogenesis and an increased risk of leukemia. Although ANKRD26 and ETV6 exhibit inverse expression during megakaryopoiesis, ETV6 does not regulate the ANKRD26 expression. Hypothesizing an interplay between ETV6 and ANKRD26 through in vitro studies, we explored the interactions between the two proteins. In this study, we found that ANKRD26 interacts with ETV6 and retains it in the cytoplasm, phenocopying ETV6-RT-related mutants. We found that GPS2, a component of the NCoR complex, binds both ANKRD26 and ETV6, mediating this interaction. Furthermore, ANKRD26 overexpression deregulates ETV6 transcriptional repression, supporting a common pathogenic mechanism underlying ANKRD26-RT, FPD/AML, and ETV6-RT. Our results unveil a novel ANKRD26-ETV6-GPS2 axis, providing new insights to investigate the molecular mechanism underlying thrombocytopenias with a predisposition to myeloid neoplasms that need to be further characterized. Full article

Immune checkpoint blockade (ICB), radiotherapy, chemotherapy and surgery are currently used as therapeutic strategies against melanoma, lung, bladder and renal cancers, but their efficacy is limited. Thus, I need to predict treatment response and resistance to address this challenge. In this study, I analyzed 350 lung cancer, 320 melanoma, 215 bladder cancer, 139 head and neck cancer and 151 renal carcinoma patients treated with ICB to identify tumor mutations associated with response and resistance to treatment. I identified several tumor mutations linked with a difference in survival outcomes following ICB. In lung cancer, missense mutations in ABL1, ASXL1, EPHA3, EPHA5, ERBB4, MET, MRE11A, MSH2, NOTCH1, PAK7, PAX5, PGR, ZFHX3, PIK3C3 and REL genes were indicative of favorable responses to ICB. Conversely, mutations in TGFBR2, ARID5B, CDKN2C, HIST1H3I, RICTOR, SMAD2, SMAD4 and TP53 genes were associated with shorter overall survival post-ICB treatment. In melanoma, mutations in FBXW7, CDK12, CREBBP, CTNNB1, NOTCH1 and RB1 genes predict resistance to ICB, whereas missense mutations in FAM46C and RHOA genes are associated with extended overall survival. In bladder cancer, mutations in HRAS genes predict resistance to ICB, whereas missense mutations in ERBB2, GNAS, ATM, CDKN2A and LATS1 genes, as well as nonsense mutations in NCOR1 and TP53 genes, are associated with extended overall survival. In head and neck cancer, mutations in genes like PIK3CA and KRAS correlated with longer survival, while mutations in genes like TERT and TP53 were linked to shorter survival. In renal carcinoma, mutations such as EPHA5, MGA, PIK3R1, PMS1, TSC1 and VHL were linked to prolonged overall survival, while others, including total splice mutations and mutations in B2M, BCOR, JUN, FH, IGF1R and MYCN genes were associated with shorter overall survival following ICB. Then, I developed predictive survival models by machine learning that correctly forecasted cancer patient survival following ICB within an error between 5 and 8 months based on their distinct tumor mutational attributes. In conclusion, this study advocates for personalized immunotherapy approaches in cancer patients. Full article

Background/Objectives: This study focused on a group of 22 elite male mountain runners from Brazil (average age of 35.9 ± 6.5 years) with the objective of exploring the possible roles of the ACTN3 R577X, ACE I/D, and CK MM A/G NcoI genetic variants in shaping electrochemical profiles and maintaining acid-base homeostasis during a 105-km ultramarathon. Methods: Genotyping for each polymorphism (ACTN3: RR, RX, XX; ACE: DD, ID, II; CK MM: AA, AG, GG) was conducted using PCR-RFLP (Polymerase Chain Reaction-Restriction Fragment Length Polymorphism), and saliva samples were used to obtain DNA. Analyses of electrochemical and acid-base disturbances were performed in real time. Results: It was observed that athletes who completed the race in less time had lower calcium concentrations (Rs = 0.35; p = 0.016). Pre-race, the RX genotype showed a 14.19% reduction in potassium levels compared to RR (p = 0.01). The GG genotype showed potassium levels 19.36% higher than AA (p = 0.01) and a 6.11% increase in hematocrit values compared to AA (p = 0.03). Additionally, the AG genotype exhibited hematocrit values 5.44% higher than AA (p = 0.03). Post-race, the XX genotype demonstrated higher hematocrit values compared to RX, with an increase of 8.92% (p = 0.03). The II genotype showed a 0.27% increase in pH compared to ID (p = 0.02) and a 20.42% reduction in carbon dioxide levels (p = 0.01). Conclusions: The findings emphasize the impact of the examined polymorphisms on the modulation of electrochemical factors and the maintenance of acid-base equilibrium in athletes during 105 km ultramarathons. Full article

Gender and biological sex have distinct impacts on the pathogenesis of type 2 diabetes (T2D). Estrogen deficiency is known to predispose female mice to T2D. In our previous study, we found that a high-fat, high-sucrose diet (HFHSD) induces T2D in male mice through the miR-10b-5p/KLF11/KIT pathway, but not in females, highlighting hormonal disparities in T2D susceptibility. However, the underlying molecular mechanisms of this hormonal protection in females remain elusive. To address this knowledge gap, we utilized ovariectomized, estrogen-deficient female mice, fed them a HFHSD to induce T2D, and investigated the molecular mechanisms involved in estrogen-deficient diabetic female mice, relevant cell lines, and female T2D patients. Initially, female mice fed a HFHSD exhibited a delayed onset of T2D, but ovariectomy-induced estrogen deficiency promptly precipitated T2D without delay. Intriguingly, insulin (INS) was upregulated, while insulin receptor (INSR) and protein kinase B (AKT) were downregulated in these estrogen-deficient diabetic female mice, indicating insulin-resistant T2D. These dysregulations of INS, INSR, and AKT were mediated by a miR-10a/b-5p-NCOR2 axis. Treatment with miR-10a/b-5p effectively alleviated hyperglycemia in estrogen-deficient T2D female mice, while β-estradiol temporarily reduced hyperglycemia. Consistent with the murine findings, plasma samples from female T2D patients exhibited significant reductions in miR-10a/b-5p, estrogen, and INSR, but increased insulin levels. Our findings suggest that estrogen protects against insulin-resistant T2D in females through miR-10a/b-5p/NCOR2 pathway, indicating the potential therapeutic benefits of miR-10a/b-5p restoration in female T2D management. Full article

The core clock gene Period2 (PER2) is associated with mammary gland development and lipid synthesis in rodents and has recently been found to have a diurnal variation in the process of lactation, but has not yet been demonstrated in bovine mammary epithelial cells (BMECs). To explore the regulatory function of PER2 on milk fat synthesis in bovine mammary epithelial cells, we initially assessed the expression of clock genes and milk fat metabolism genes for 24 h using real-time quantitative PCR and fitted the data to a cosine function curve. Subsequently, we overexpressed the PER2 in BMECs using plasmid vector (pcDNA3.1-PER2), with empty vector pcDNA3.1-myc as the control. After transfecting BMECs for 48 h, we assessed the protein abundance related to milk fat synthesis by Western blot, the expression of genes coding for these proteins using real time-quantitative PCR, the production of triacylglycerol, and the fatty acid profile. The findings indicated that a total of nine clock genes (PER1/2, CRY1/2, REV-ERBα, BMAL1, NCOR1, NR2F2, FBXW11), seven fatty acid metabolism genes (CD36, ACSS2, ACACA, SCD, FADS1, DGAT1, ADFP), and six nuclear receptor-related genes (INSIG1, SCAP, SREBF1, C/EBP, PPARG, LXR) exhibited oscillation with a period close to 24 h in non-transfected BMECs (R² ≥ 0.7). Compared to the control group (transfected with empty pcDNA3.1-myc), the triglyceride content significantly increased in the PER2 overexpression group (p < 0.05). The lipogenic genes for fatty acid transport and triglyceride synthesis (ACACA, SCD, LPIN1, DGAT1, and SREBF1) were upregulated after PER2 overexpression, along with the upregulation of related protein abundance (p < 0.05). The contents and ratios of palmitic acid (C16:0), oleic acid (C18:1n9c), and trans-oleic acid (C18:1n9t) were significantly increased in the overexpression group (p < 0.05). Overall, the data supported that PER2 participated in the process of milk fat metabolism and is potentially involved in the de novo synthesis and desaturation of fatty acid in bovine mammary epithelial cells. Full article

Histone deacetylases (HDACs) are important cancer drug targets. Existing FDA-approved drugs target the catalytic pocket of HDACs, which is conserved across subfamilies (classes) of HDAC. However, engineering specificity is an important goal. Herein, we use molecular modeling approaches to identify and target potential novel pockets specific to Class IIA HDAC-HDAC4 at the interface between HDAC4 and the transcriptional corepressor component protein NCoR. These pockets were screened using an ensemble docking approach combined with consensus scoring to identify compounds with a different binding mechanism than the currently known HDAC modulators. Binding was compared in experimental assays between HDAC4 and HDAC3, which belong to a different family of HDACs. HDAC4 was significantly inhibited by compound 88402 but not HDAC3. Two other compounds (67436 and 134199) had IC50 values in the low micromolar range for both HDACs, which is comparable to the known inhibitor of HDAC4, SAHA (Vorinostat). However, both of these compounds were significantly weaker inhibitors of HDAC3 than SAHA and thus more selective, albeit to a limited extent. Five compounds exhibited activity on human breast carcinoma and/or urothelial carcinoma cell lines. The present result suggests potential mechanistic and chemical approaches for developing selective HDAC4 modulators. Full article

Keratin-positive giant cell-rich tumor (KPGCT) is an extremely rare and recently described mesenchymal neoplasm that occurs in both soft tissue and bone, frequently found in young women. It has locally recurrent potential if incompletely excised but low risk for metastasis. KPGCT is histologically similar to conventional giant cell tumors of soft tissue but shows the presence of keratin-positive mononuclear cells. Interestingly, KPGCT also shares some morphological features with xanthogranulomatous epithelial tumors. These two tumors have recently been shown to harbor an HMGA2–NCOR2 fusion, arguing in favor of a single entity. Surgery is the treatment of choice for localized KPGCT. Therapeutic options for advanced or metastatic disease are unknown. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology, and treatment of KPGCT. In addition, we will discuss the differential diagnosis of this emerging entity. Full article

Prostate cancer is a highly heterogeneous disease and mortality is mainly due to metastases but the initial steps of metastasis have not been well characterized. We have performed integrative whole exome sequencing and transcriptome analysis of primary prostate tumor foci and corresponding lymph node metastases (LNM) from 43 patients enrolled in clinical trial. We present evidence that, while there are some cases of clonally independent primary tumor foci, 87% of primary tumor foci and metastases are descended from a common ancestor. We demonstrate that genes related to oxidative phosphorylation are upregulated in LNM and in African-American patients relative to White patients. We further show that mutations in TP53, FLT4, EYA1, NCOR2, CSMD3, and PCDH15 are enriched in prostate cancer metastases. These findings were validated in a meta-analysis of 3929 primary tumors and 2721 metastases and reveal a pattern of molecular alterations underlying the pathology of metastatic prostate cancer. We show that LNM contain multiple subclones that are already present in primary tumor foci. We observed enrichment of mutations in several genes including understudied genes such as EYA1, CSMD3, FLT4, NCOR2, and PCDH15 and found that mutations in EYA1 and CSMD3 are associated with a poor outcome in prostate cancer. Full article

Cancer is a genomic disease, with driver mutations contributing to tumorigenesis. These potentially heritable variants influence risk and underlie familial breast cancer (BC). This study evaluated associations between BC risk and 13 SNPs in driver genes MAP3K1, SF3B1, SMAD4, ARID2, ATR, KMT2C, MAP3K13, NCOR1, and TBX3, in BRCA1/2-negative Chilean families. SNPs were genotyped using TaqMan Assay in 492 cases and 1285 controls. There were no associations between rs75704921:C>T (ARID2); rs2229032:A>C (ATR); rs3735156:C>G (KMT2C); rs2276738:G>C, rs2293906:C>T, rs4075943T:>A, rs13091808:C>T (MAP3K13); rs178831:G>A (NCOR1); or rs3759173:C>A (TBX3) and risk. The MAP3K1 rs832583 A allele (C/A+A/A) showed a protective effect in families with moderate BC history (OR = 0.7 [95% CI 0.5–0.9] p = 0.01). SF3B1 rs16865677-T (G/T+T/T) increased risk in sporadic early-onset BC (OR = 1.4 [95% CI 1.0–2.0] p = 0.01). SMAD4 rs3819122-C (A/C+C/C) increased risk in cases with moderate family history (OR = 2.0 [95% CI 1.3–2.9] p ≤ 0.0001) and sporadic cases diagnosed ≤50 years (OR = 1.6 [95% CI 1.1–2.2] p = 0.006). SMAD4 rs12456284:A>G increased BC risk in G-allele carriers (A/G + G/G) in cases with ≥2 BC/OC cases and early-onset cases (OR = 1.2 [95% CI 1.0–1.6] p = 0.04 and OR = 1.4 [95% CI 1.0–1.9] p = 0.03, respectively). Our study suggests that specific germline variants in driver genes MAP3K1, SF3B1, and SMAD4 contribute to BC risk in Chilean population. Full article

Psoriasis is a chronic immune-mediated skin disease in which the symptom-free, uninvolved skin carries alterations in gene expression, serving as a basis for lesion formation. Histones and histone acetylation-related processes are key regulators of gene expression, controlling cell proliferation and immune responses. Dysregulation of these processes is likely to play an important role in the pathogenesis of psoriasis. To gain a complete overview of these potential alterations, we performed a meta-analysis of a psoriatic uninvolved skin dataset containing differentially expressed transcripts from nearly 300 individuals and screened for histones and histone acetylation-related molecules. We identified altered expression of the replication-dependent histones HIST2H2AA3 and HIST2H4A and the replication-independent histones H2AFY, H2AFZ, and H3F3A/B. Eight histone chaperones were also identified. Among the histone acetyltransferases, ELP3 and KAT5 and members of the ATAC, NSL, and SAGA acetyltransferase complexes are affected in uninvolved skin. Histone deacetylation-related alterations were found to affect eight HDACs and members of the NCOR/SMRT, NURD, SIN3, and SHIP HDAC complexes. In this article, we discuss how histone and histone acetylation-related expression changes may affect proliferation and differentiation, as well as innate, macrophage-mediated, and T cell-mediated pro- and anti-inflammatory responses, which are known to play a central role in the development of psoriasis. Full article