Ligand-dependent Nuclear Receptor Research Articles

The androgen receptor in mesenchymal progenitors regulates skeletal muscle mass via Igf1 expression in male mice

Androgens exert their effects primarily by binding to the androgen receptor (AR), a ligand-dependent nuclear receptor. While androgens have anabolic effects on skeletal muscle, previous studies reported that AR functions in myofibers to regulate skeletal muscle quality, rather than skeletal muscle mass. Therefore, the anabolic effects of androgens are exerted via nonmyofiber cells. In this context, the cellular and molecular mechanisms of AR in mesenchymal progenitors, which play a crucial role in maintaining skeletal muscle homeostasis, remain largely unknown. In this study, we demonstrated expression of AR in mesenchymal progenitors and found that targeted AR ablation in mesenchymal progenitors reduced limb muscle mass in mature adult, but not young or aged, male mice, although fatty infiltration of muscle was not affected. The absence of AR in mesenchymal progenitors led to remarkable perineal muscle hypotrophy, regardless of age, due to abnormal regulation of transcripts associated with cell death and extracellular matrix organization. Additionally, we revealed that AR in mesenchymal progenitors regulates the expression of insulin-like growth factor 1 (Igf1) and that IGF1 administration prevents perineal muscle atrophy in a paracrine manner. These findings indicate that the anabolic effects of androgens regulate skeletal muscle mass via, at least in part, AR signaling in mesenchymal progenitors.

Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta.

Thyroxine receptor beta (TRβ) is a ligand-dependent nuclear receptor that participates in regulating multiple biological processes, particularly playing an important role in lipid metabolism regulation. TRβ is currently a popular therapeutic target for nonalcoholic steatohepatitis (NASH), while no drugs have been approved to treat this disease. MGL-3196 (Resmetirom) is the first TRβ agonist that has succeeded in phase III clinical trials for the treatment of NASH; therefore, studying its molecular mechanism of action is of great significance. In this study, we employed molecular dynamic simulation to investigate the interaction mode between MGL-3196 and TRβ at the all-atom level. More importantly, by comparing the binding patterns of MGL-3196 in several prevalent TRβ mutants, it was identified that the mutations R243Q and H435R located, respectively, around and within the ligand-binding pocket of TRβ cause TRβ to be insensitive to MGL-3196. This indicates that patients with NASH carrying these two mutations may exhibit resistance to the medication of MGL-3196, thereby highlighting the potential impact of TRβ mutations on TRβ-targeted treatment of NASH and beyond.

Reprogramming of the LXRα Transcriptome Sustains Macrophage Secondary Inflammatory Responses.

Macrophages regulate essential aspects of innate immunity against pathogens. In response to microbial components, macrophages activate primary and secondary inflammatory gene programs crucial for host defense. The liver X receptors (LXRα, LXRβ) are ligand-dependent nuclear receptors that direct gene expression important for cholesterol metabolism and inflammation, but little is known about the individual roles of LXRα and LXRβ in antimicrobial responses. Here, the results demonstrate that induction of LXRα transcription by prolonged exposure to lipopolysaccharide (LPS) supports inflammatory gene expression in macrophages. LXRα transcription is induced by NF-κB and type-I interferon downstream of TLR4 activation. Moreover, LPS triggers a reprogramming of the LXRα cistrome that promotes cytokine and chemokine gene expression through direct LXRα binding to DNA consensus sequences within cis-regulatory regions including enhancers. LXRα-deficient macrophages present fewer binding of p65 NF-κB and reduced histone H3K27 acetylation at enhancers of secondary inflammatory response genes. Mice lacking LXRα in the hematopoietic compartment show impaired responses to bacterial endotoxin in peritonitis models, exhibiting reduced neutrophil infiltration and decreased expansion and inflammatory activation of recruited F4/80lo-MHC-IIhi peritoneal macrophages. Together, these results uncover a previously unrecognized function for LXRα-dependent transcriptional cis-activation of secondary inflammatory gene expression in macrophages and the host response to microbial ligands.

Dynamic observation of circRNA and mRNA profiles in a rat model of deep vein thrombosis.

The goal of the present study was to identify different transcriptome expression profiles involved in the pathogenesis of deep vein thrombosis (DVT), and to illustrate the diagnostic and therapeutic potential of circular RNAs (circRNAs) and mRNAs in DVT progression. A Sprague-Dawley rat model of DVT was successfully established through the stenosis method and samples were sequenced at four time points (1, 6 and 12 h, and 3 days after ligation) to observe the dynamic changes in circRNAs and mRNAs during DVT progression. RNA sequencing was used to analyze the circRNA and mRNA expression profiles, and associated functions and pathways, in the blood of DVT rats at the four time points. In addition, Short Time Series Expression Miner (STEM) analysis was performed to explore temporal gene expression. Differential expression of 1,680, 4,018, 3,724, and 3,036 circRNAs, and 400, 1,176, 373, and 573 mRNAs was observed in the 1, 6 and 12 h, and 3-day groups, respectively, compared with the sham group (fold change >2.0 or <-2.0, P<0.05). Functional enrichment analysis indicated that differentially expressed mRNAs were associated with the following terms: Immune response, cell activation, blood stasis facilitated organelle, extracellular membrane-bounded organelle, and blood microparticle, oxygen transporter activity. STEM analysis indicated that the expression of 366 circRNAs in circRNA profile 45 and 270 mRNAs in mRNA profile 45 was consistent with thrombus progression. Enrichment analysis was performed on mRNA profile 45. The main Gene Ontology annotations were chromosome segregation, mitotic sister chromatid segregation, cell cycle process, and ligand-dependent nuclear receptor transcription coactivator activity. Pathway enrichment analysis identified the platelet-associated pathway, immune-associated pathway, and inflammation-relation pathway. According to the enriched platelet-associated pathways, four mRNAs and ten candidate circRNAs were selected for reverse transcription-quantitative PCR verification. The expression of nine of the ten circRNAs and all four mRNAs was consistent with the sequencing results. In summary, differentially expressed circRNAs and mRNAs are dynamically involved in DVT development. Dysregulated transcriptome profiles and the corresponding functions and pathways may provide mechanistic insights into DVT diagnosis and treatment.

Molecular characterization and potential function of Rxrγ in gonadal differentiation of Chinese soft-shelled turtle (Pelodiscus sinensis)

Retinoid X receptor (RXR) is a member of the ligand-dependent nuclear receptor family. Previous studies revealed that RXRs are involved in reproduction in vertebrates. However, information on the function of RXRs in turtles is scarce. In this study, the Rxrγ cDNA sequence of Pelodiscus sinensis was cloned and analyzed, and a polyclonal antibody was constructed. RXRγ protein showed a positive signal in both mature and differentiated gonads of the turtle. Subsequently, the function of the Rxrγ gene in gonadal differentiation was confirmed using short interfering RNA (RNAi). The full-length cDNA sequence of the Rxrγ gene in P. sinensis was 2152 bp, encoding 407 amino acids and containing typical nuclear receptor family domains, including the DNA-binding domain (DBD), ligand-binding domain (LBD), and activation function 1 (AF1). Moreover, gonadal Ps-Rxrγ showed sexual dimorphism expression patterns in differentiated gonads. Real-time quantitative PCR results revealed that the Rxrγ gene was highly expressed in the turtle ovary. RNAi treatment increased the number of Sertoli cells in ZZ embryonic gonads. Furthermore, RNA interference upregulated Dmrt1 and Sox9 in ZZ and ZW embryonic gonads. However, Foxl2, Cyp19a1, Stra8, and Cyp26b1 were downregulated in embryonic gonads. The results indicated that Rxrγ participated in gonadal differentiation and development in P. sinensis.

Filarial DAF-12 sense the host serum to resume iL3 development during infection.

Nematode parasites enter their definitive host at the developmentally arrested infectious larval stage (iL3), and the ligand-dependent nuclear receptor DAF-12 contributes to trigger their development to adulthood. Here, we characterized DAF-12 from the filarial nematodes Brugia malayi and Dirofilaria immitis and compared them with DAF-12 from the non-filarial nematodes Haemonchus contortus and Caenorhabditis elegans. Interestingly, Dim and BmaDAF-12 exhibit high sequence identity and share a striking higher sensitivity than Hco and CelDAF-12 to the natural ligands Δ4- and Δ7-dafachronic acids (DA). Moreover, sera from different mammalian species activated specifically Dim and BmaDAF-12 while the hormone-depleted sera failed to activate the filarial DAF-12. Accordingly, hormone-depleted serum delayed the commencement of development of D. immitis iL3 in vitro. Consistent with these observations, we show that spiking mouse charcoal stripped-serum with Δ4-DA at the concentration measured in normal mouse serum restores its capacity to activate DimDAF-12. This indicates that DA present in mammalian serum participate in filarial DAF-12 activation. Finally, analysis of publicly available RNA sequencing data from B. malayi showed that, at the time of infection, putative gene homologs of the DA synthesis pathways are coincidently downregulated. Altogether, our data suggest that filarial DAF-12 have evolved to specifically sense and survive in a host environment, which provides favorable conditions to quickly resume larval development. This work sheds new light on the regulation of filarial nematodes development while entering their definitive mammalian host and may open the route to novel therapies to treat filarial infections.

Ancient segmentally duplicated LCORL retrocopies in equids.

LINE-1 is an active transposable element encoding proteins capable of inserting host gene retrocopies, resulting in retro-copy number variants (retroCNVs) between individuals. Here, we performed retroCNV discovery using 86 equids and identified 437 retrocopy insertions. Only 5 retroCNVs were shared between horses and other equids, indicating that the majority of retroCNVs inserted after the species diverged. A large number (17-35 copies) of segmentally duplicated Ligand Dependent Nuclear Receptor Corepressor Like (LCORL) retrocopies were present in all equids but absent from other extant perissodactyls. The majority of LCORL transcripts in horses and donkeys originate from the retrocopies. The initial LCORL retrotransposition occurred 18 million years ago (17-19 95% CI), which is coincident with the increase in body size, reduction in digit number, and changes in dentition that characterized equid evolution. Evolutionary conservation of the LCORL retrocopy segmental amplification in the Equidae family, high expression levels and the ancient timeline for LCORL retrotransposition support a functional role for this structural variant.

Molecular basis of ligand-dependent Nurr1-RXRα activation.

Small molecule compounds that activate transcription of Nurr1-RXRα (NR4A2-NR2B1) nuclear receptor heterodimers are implicated in the treatment of neurodegenerative disorders, but function through poorly understood mechanisms. Here, we show that RXRα ligands activate Nurr1-RXRα through a mechanism that involves ligand-binding domain (LBD) heterodimer protein-protein interaction (PPI) inhibition, a paradigm distinct from classical pharmacological mechanisms of ligand-dependent nuclear receptor modulation. NMR spectroscopy, protein-protein interaction, cellular transcription assays show that Nurr1-RXRα transcriptional activation by RXRα ligands is not correlated with classical RXRα agonism but instead correlated with weakening Nurr1-RXRα LBD heterodimer affinity and heterodimer dissociation. Our data inform a model by which pharmacologically distinct RXRα ligands (agonists and Nurr1-RXRα selective agonists that function as RXRα antagonists) operate as allosteric PPI inhibitors that release a transcriptionally active Nurr1 monomer from a repressive Nurr1-RXRα heterodimeric complex. These findings provide a molecular blueprint for ligand activation of Nurr1 transcription via small molecule targeting of Nurr1-RXRα.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Prognostic biomarkers in and selection of surgical patients with hepatocellular carcinoma.

Height-Related Polygenic Variants Are Associated with Metabolic Syndrome Risk and Interact with Energy Intake and a Rice-Main Diet to Influence Height in KoGES

Adult height is inversely related to metabolic syndrome (MetS) risk, but its genetic impacts have not been revealed. The present study aimed to examine the hypothesis that adult height-related genetic variants interact with lifestyle to influence adult height and are associated with MetS risk in adults aged >40 in Korea during 2010-2014. Participants were divided into short stature (SS; control) and tall stature (TS; case) by the 85th percentile of adult height. The genetic variants linked to adult height were screened from a genome-wide association study in a city hospital-based cohort (n = 58,701) and confirmed in Ansan/Ansung plus rural cohorts (n = 13,783) among the Korean Genome and Epidemiology Study. Genetic variants that interacted with each other were identified using the generalized multifactor dimensionality reduction (GMDR) analysis. The interaction between the polygenic risk score (PRS) of the selected genetic variants and lifestyles was examined. Adult height was inversely associated with MetS, cardiovascular diseases, and liver function. The PRS, including zinc finger and BTB domain containing 38 (ZBTB38)_rs6762722, polyadenylate-binding protein-interacting protein-2B (PAIP2B)_rs13034890, carboxypeptidase Z (CPZ)_rs3756173, and latent-transforming growth factor beta-binding protein-1 (LTBP1)_rs4630744, was positively associated with height by 1.29 times and inversely with MetS by 0.894 times after adjusting for covariates. In expression quantitative trait loci, the gene expression of growth/differentiation factor-5 (GDF5)_rs224331, non-SMC condensin I complex subunit G (NCAPG)_rs2074974, ligand-dependent nuclear receptor corepressor like (LCORL)_rs7700107, and insulin-like growth factor-1 receptor (IGF1R)_rs2871865 was inversely linked to their risk allele in the tibial nerve and brain. The gene expression of PAIP2B_rs13034890 and a disintegrin and metalloproteinase with thrombospondin motifs-like-3 (ADAMTSL3)_rs13034890 was positively related to it. The PRS was inversely associated with MetS, hyperglycemia, HbA1c, and white blood cell counts. The wild type of GDF5_rs224331 (Ala276) lowered binding energy with rugosin A, D, and E (one of the hydrolyzable tannins) but not the mutated one (276Ser) in the in-silico analysis. The PRS interacted with energy intake and rice-main diet; PRS impact was higher in the high energy intake and the low rice-main diet. In conclusion, the PRS for adult height interacted with energy intake and diet patterns to modulate height and was linked to height and MetS by modulating their expression in the tibial nerve and brain.

The role of peroxisome proliferator-activated receptors in the modulation of hyperinflammation induced by SARS-CoV-2 infection: A perspective for COVID-19 therapy.

Coronavirus disease 2019 (COVID-19) is a severe respiratory disease caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that affects the lower and upper respiratory tract in humans. SARS-CoV-2 infection is associated with the induction of a cascade of uncontrolled inflammatory responses in the host, ultimately leading to hyperinflammation or cytokine storm. Indeed, cytokine storm is a hallmark of SARS-CoV-2 immunopathogenesis, directly related to the severity of the disease and mortality in COVID-19 patients. Considering the lack of any definitive treatment for COVID-19, targeting key inflammatory factors to regulate the inflammatory response in COVID-19 patients could be a fundamental step to developing effective therapeutic strategies against SARS-CoV-2 infection. Currently, in addition to well-defined metabolic actions, especially lipid metabolism and glucose utilization, there is growing evidence of a central role of the ligand-dependent nuclear receptors and peroxisome proliferator-activated receptors (PPARs) including PPARα, PPARβ/δ, and PPARγ in the control of inflammatory signals in various human inflammatory diseases. This makes them attractive targets for developing therapeutic approaches to control/suppress the hyperinflammatory response in patients with severe COVID-19. In this review, we (1) investigate the anti-inflammatory mechanisms mediated by PPARs and their ligands during SARS-CoV-2 infection, and (2) on the basis of the recent literature, highlight the importance of PPAR subtypes for the development of promising therapeutic approaches against the cytokine storm in severe COVID-19 patients.

Mechanistic insights into the peroxisome proliferator-activated receptor alpha as a transcriptional suppressor.

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent hepatic disorders that 20-30% of the world population suffers from. The feature of NAFLD is excess lipid accumulation in the liver, exacerbating multiple metabolic syndromes such as hyperlipidemia, hypercholesterolemia, hypertension, and type 2 diabetes. Approximately 20-30% of NAFLD cases progress to more severe chronic hepatitis, known as non-alcoholic steatohepatitis (NASH), showing deterioration of hepatic functions and liver fibrosis followed by cirrhosis and cancer. Previous studies uncovered that several metabolic regulators had roles in disease progression as key factors. Peroxisome proliferator-activated receptor alpha (PPARα) has been identified as one of the main players in hepatic lipid homeostasis. PPARα is abundantly expressed in hepatocytes, and is a ligand-dependent nuclear receptor belonging to the NR1C nuclear receptor subfamily, orchestrating lipid/glucose metabolism, inflammation, cell proliferation, and carcinogenesis. PPARα agonists are expected to be novel prescription drugs for NASH treatment, and some of them (e.g., Lanifibranor) are currently under clinical trials. These potential novel drugs are developed based on the knowledge of PPARα-activating target genes related to NAFLD and NASH. Intriguingly, PPARα is known to suppress the expression of subsets of target genes under agonist treatment; however, the mechanisms of PPARα-mediated gene suppression and functions of these genes are not well understood. In this review, we summarize and discuss the mechanisms of target gene repression by PPARα and the roles of repressed target genes on hepatic lipid metabolism, fibrosis and carcinogenesis related to NALFD and NASH, and provide future perspectives for PPARα pharmaceutical potentials.

Low 15d-PGJ2 status is associated with oxidative stress in chronic obstructive pulmonary disease patients.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-dependent nuclear receptor and highly expressed in human and rodent lungs. 15-Deoxy-delta-12,14-prostaglandin J2 (15d-PGJ2), known for cyclopentenone prostaglandin, is the endogenous ligand of PPARγ. However, the associations among PPARγ, 15d-PGJ2 and chronic obstructive pulmonary disease (COPD) were unclear. All 130 fasting blood samples and 40 lung specimens were obtained from COPD patients and control subjects. Serum 15d-PGJ2 was detected by ELISA. The expressions of oxidative stress indicators were measured using western blotting and PPARγ nuclei were evaluated with immunohistochemistry in lungs. The associations among serum 15d-PGJ2, pulmonary PPARγ and oxidative stress indicators, and COPD were estimated. Serum 15d-PGJ2 was reduced in COPD patients compared with healthy volunteers. Linear and logistic regression analysis indicated that serum 15d-PGJ2 was positively associated with pulmonary function in COPD patients. In addition, PPARγ-positive nuclei were reduced and oxidative stress indicators, included HO-1 and NOX-4, were increased in lungs of COPD patients. Further correlative analysis suggested that pulmonary function parameters was positively correlated with serum 15d-PGJ2 and pulmonary PPARγ-positive nuclei, inversely related to oxidative stress indicators in lungs of COPD patients. Pretreatment with 15d-PGJ2 obviously attenuated TNFα-induced oxidative stress in BEAS-2B cells. Serum 15d-PGJ2 and pulmonary PPARγ are reduced, and oxidative stress is elevated in COPD patients. Serum 15d-PGJ2 is inversely associated with oxidative stress in COPD patients.

A Novel A > G Polymorphism in the Intron 1 of LCORL Gene Is Significantly Associated with Hide Weight and Body Size in Dezhou Donkey

Simple SummaryThe annual shortage of donkey hides is significant in China. Therefore, to meet the market demand, it is important to improve donkey hide production through molecular breeding. In this study, one SNP was identified in intron 1 of the LCORL gene, and polymorphism information content (PIC) was moderate in the population. The association analysis of g.112558859 A > G with body height, body length, chest circumference and hide weight was conducted and found to be significantly associated with these traits. The hide weight of donkeys with the GG genotype was 1.07 Kg heavier than those with AA genotype. This provides the foundation for breeding large donkey breeds with high hide production.Several studies have shown the association between the ligand-dependent nuclear receptor compression-like protein (LCORL) gene and body size in horses, pigs and donkeys. Based on previous studies, the LCORL gene was hypothesized to be associated with growth traits and hide weight in Dezhou donkeys. In this study, we aimed to reveal the variation of the LCORL gene in the Dezhou donkey and explore whether the gene is associated with hide weight and body size. In this study, genetic polymorphisms in the LCORL gene of the Dezhou donkey were studied using targeted sequencing technology, and single nucleotide polymorphisms (SNPs) of the LCORL gene were analyzed for association with hide weight and body size in Dezhou donkeys. The results showed that there was an SNP locus situated in intron 1 of the LCORL gene. Association analysis revealed that individuals with the GG genotype had significantly higher body height, body length, chest circumference and hide weight than those with the AA genotype (p < 0.05). Therefore, the g.112558859 A > G locus can be used as a potential candidate marker affecting body size and hide weight. This study provides the foundation for breeding high-quality donkeys with high hide yield.

Impact of Phytochemicals on PPAR Receptors: Implications for Disease Treatments.

Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.

Fenofibrate mediated activation of PPARα negatively regulates trophoblast invasion

The Peroxisome Proliferator-Activated Receptor-alpha (PPARα) is a member of the ligand-dependent nuclear receptor superfamily known for their crucial role in lipid metabolism. The expression and role of PPARα in trophoblast cells are not very well known. Trophoblast invasion is one of the most critical processes required for successful implantation of the developing embryo into the maternal endometrium. Defects in this process are associated with adverse pregnancy outcomes such as FGR(Fetal Growth Restriction), Preeclampsia, and choriocarcinoma. In this present study, we investigated the role of the ligand-activated transcription factor, Peroxisome proliferator-activated receptor (PPARα) in regulating trophoblast cell invasion using cell lines and explants-based models. Immunohistological localization of PPARα in human placental tissues showed a gestational variation with relatively low expression at term as compared to early trimester. PCR and Western Blot also confirmed this. Further to delineate the effect of PPAR alpha on trophoblast invasion, EVT derived HTR8/SVneo cell lines were stimulated with PPARα agonist, i.e., fenofibrate (FF). Fenofibrate stimulation led to an increased activation and nuclear translocation of PPARα, followed by reduced migration and invasion of these cells in a matrigel invasion assay (Boyden chamber). PPAR alpha stimulation also led to a reduced MMP-2/9 expression following our previous observation. Thus, we may conclude that PPARα to be playing a very important regulatory role in orchestrating the invasive trophoblast programme and hence it seems plausible for it to be associated with PE, which is often characterized by a shallow trophoblast invasion.

Comparative Enhancer Map of Cattle Muscle Genome Annotated by ATAC-Seq

Annotating regulatory elements could benefit the interpretation of the molecular mechanism of genome-wide association study (GWAS) hits. In this work, we performed transposase-accessible chromatin with sequencing (ATAC-seq) to annotate the cattle muscle genome's functional elements. A total of 10,023 and 11,360 peaks were revealed in muscle genomes of adult and embryo cattle, respectively. The two peak sets produced 8,850 differentially accessible regions (DARs), including 2,515 promoters and 4,319 putative enhancers. These functional elements were associated with the cell cycle, muscle development, and lipid metabolism. A total of 15 putative enhancers were selected for a dual-luciferase reporter assay, and 12 of them showed enhancer activity in cattle myoblasts. Interestingly, the GeneHancer database has annotated the interactions of eight active enhancers with gene promoters, such as embryo-specific peak1053 (log2FC = 1.81, embryo/adult, E/A) with ligand-dependent nuclear receptor corepressor-like protein (LCORL) and embryo-specific peak4218 (log2FC = 1.81) with FERM domain-containing 8 (FRMD8). A total of 295 GWAS loci from the animal QTL database were mapped to 183 putative enhancers, including rs109554838 (associated with cattle body weight and average daily gain) to peak1053 and rs110294629 (associated with beef shear force and tenderness score) to peak4218. Notably, peak4218 has been found to be involved in mouse embryo development. Deleting peak4218 clearly reduced luciferase activity (P = 3.30E-04). Our comparative enhancer map is expected to benefit the area of beef cattle breeding.

Role of Phytoconstituents as PPAR Agonists: Implications for Neurodegenerative Disorders.

Peroxisome proliferator-activated receptors (PPAR-γ, PPAR-α, and PPAR-β/δ) are ligand-dependent nuclear receptors that play a critical role in the regulation of hundreds of genes through their activation. Their expression and targeted activation play an important role in the treatment of a variety of diseases, including neurodegenerative, cardiovascular, diabetes, and cancer. In recent years, several reviews have been published describing the therapeutic potential of PPAR agonists (natural or synthetic) in the disorders listed above; however, no comprehensive report defining the role of naturally derived phytoconstituents as PPAR agonists targeting neurodegenerative diseases has been published. This review will focus on the role of phytoconstituents as PPAR agonists and the relevant preclinical studies and mechanistic insights into their neuroprotective effects. Exemplary research includes flavonoids, fatty acids, cannabinoids, curcumin, genistein, capsaicin, and piperine, all of which have been shown to be PPAR agonists either directly or indirectly. Additionally, a few studies have demonstrated the use of clinical samples in in vitro investigations. The role of the fruit fly Drosophila melanogaster as a potential model for studying neurodegenerative diseases has also been highlighted.

Role of Sex on the Genetic Susceptibility to Childhood Asthma in Latinos and African Americans.

Asthma is a respiratory disease whose prevalence changes throughout the lifespan and differs by sex, being more prevalent in males during childhood and in females after puberty. In this study, we assessed the influence of sex on the genetic susceptibility to childhood asthma in admixed populations. Sex-interaction and sex-stratified genome-wide association studies (GWAS) were performed in 4291 Latinos and 1730 African Americans separately, and results were meta-analyzed. Genome-wide (p ≤ 9.35 × 10−8) and suggestive (p ≤ 1.87 × 10−6) population-specific significance thresholds were calculated based on 1000 Genomes Project data. Additionally, protein quantitative trait locus (pQTL) information was gathered for the suggestively associated variants, and enrichment analyses of the proteins identified were carried out. Four independent loci showed interaction with sex at a suggestive level. The stratified GWAS highlighted the 17q12-21 asthma locus as a contributor to asthma susceptibility in both sexes but reached genome-wide significance only in females (p-females < 9.2 × 10−8; p-males < 1.25 × 10−2). Conversely, genetic variants upstream of ligand-dependent nuclear receptor corepressor-like gene (LCORL), previously involved in height determination and spermatogenesis, were associated with asthma only in males (minimum p = 5.31 × 10−8 for rs4593128). Enrichment analyses revealed an overrepresentation of processes related to the immune system and highlighted differences between sexes. In conclusion, we identified sex-specific polymorphisms that could contribute to the differences in the prevalence of childhood asthma between males and females.

FLII and MLL1 Cooperatively Regulate Aryl Hydrocarbon Receptor-Mediated Transcription in ARPE-19 Cells.

Aryl hydrocarbon receptors (AHRs), a class of ligand-dependent nuclear receptors that regulate cellular responses by inducing the expression of various target genes in response to external signals, are implicated in maintaining retinal tissue homeostasis. Previous studies have shown that the regulation of AHR-induced gene expression requires transcriptional co-regulators. However, it is not yet clear how chromatin remodelers, histone methyltransferases and coactivators interact during AHR-mediated gene expression in human retinal cells. In this study, we reveal that the histone methyltransferase MLL1 and the coactivator FLII are involved in AHR-mediated gene expression in retinal pigment epithelial cells. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) significantly increased the expression of CYP1A1, CYP1B1 and AHRR in ARPE-19 cells, whereas FLII or MLL1 depletion significantly reduced the expression of these genes induced by TCDD. Mechanistically, FLII binds to AHR in a ligand-dependent manner in ARPE-19 cells. In particular, the binding of FLII to MLL1 occurs through the GelB domain of FLII. In addition, MLL1 binds to AHR in a ligand-independent manner. FLII is involved in the recruitment of the BRG1 chromatin remodeler and MLL1 histone methyltransferase to the AHR-regulated CYP1A1 gene region in ARPE-19 cells and consequently, plays an important role in RNA polymerase II binding and transcriptional activity by modulating chromatin accessibility. Our results identify the functions and mechanisms of action of FLII and MLL1 in AHR-induced gene expression in human retinal pigment epithelial cells.