BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.
Proliferation and/or depletion of clusters of specific bacteria regulate intestinal functions and may interfere with neuro-immune communication and behavior in patients with autism spectrum disorder (ASD). Consistently, qualitative and quantitative alteration of bacterial metabolites may functionally affect ASD pathophysiology. Up to date, age-restricted cohort studies, that may potentially help to identify specific microbial signatures in ASD, are lacking. We investigated the gut microbiota (GM) structure and fecal short chain fatty acids (SCFAs) levels in a cohort of young children (2–4 years of age) with ASD, with respect to age-matched neurotypical healthy controls. Strong increase of Bacteroidetes and Proteobacteria and decrease of Actinobacteria was observed in these patients. Among the 91 OTUs whose relative abundance was altered in ASD patients, we observed a striking depletion of Bifidobacterium longum, one of the dominant bacteria in infant GM and, conversely, an increase of Faecalibacterium prausnitzii, a late colonizer of healthy human gut and a major butyrate producer. High levels of F. prausnitzii were associated to increase of fecal butyrate levels within normal range, and over representation of KEGG functions related to butyrate production in ASD patients. Here we report unbalance of GM structure with a shift in colonization by gut beneficial bacterial species in ASD patients as off early childhood.
Insects could be potential nutritional sources both for humans and animals. Among these, Hermetia illucens, with good amount of chitin and proteins, represents a suitable diet replacement for laying hens. Little is known about insect diet effects on the microbial ecology of the gastrointestinal tract and bacterial metabolites production. In this study we investigated the effect of H. illucens larvae meal administration on cecal microbiota and short chain fatty acids (SCFAs) production in laying hens. 16S rDNA sequencing showed strong differences between cecal microbiota of soybean (SD) and insect diet (ID) groups both in type and relative abundance (unweighted and weighted beta diversity) of microbial species. In particular, Bacteroides plebeius, Elusimicrobium minutum, Alkaliphilus transvaalensis, Christensenella minuta, Vallitalea guaymasensis and Flavonifractor plautii represented the principal contributors of changes in gut microbiota composition of ID group (FDR p-values < 0.05). Of these, F. plautii, C. minuta and A. transvaalensis have the potential to degrade the chitin’s insect meal and correlated with the observed high levels of gut SCFAs produced in ID group. These microorganisms may thus connect the chitin degradation with high SCFAs production. Our results suggest H. illucens as a potential prebiotic by well feeding gut microbiota.
Alterations of microbiota-gut-brain axis have been invoked in the pathogenesis of autism spectrum disorders (ASD). Mouse models could represent an excellent tool to understand how gut dysbiosis and related alterations may contribute to autistic phenotype. In this study we paralleled gut microbiota (GM) profiles, behavioral characteristics, intestinal integrity and immunological features of colon tissues in BTBR T + tf/J (BTBR) inbred mice, a well established animal model of ASD. Sex differences, up to date poorly investigated in animal models, were specifically addressed. Results showed that BTBR mice of both sexes presented a marked intestinal dysbiosis, alterations of behavior, gut permeability and immunological state with respect to prosocial C57BL/6j (C57) strain. Noticeably, sex-related differences were clearly detected. We identified Bacteroides, Parabacteroides, Sutterella, Dehalobacterium and Oscillospira genera as key drivers of sex-specific gut microbiota profiles associated with selected pathological traits. Taken together, our findings indicate that alteration of GM in BTBR mice shows relevant sex-associated differences and supports the use of BTBR mouse model to dissect autism associated microbiota-gut-brain axis alteration.
We have identified a novel human gene encoding a 59-kDa POZ-AT hook-zinc finger protein (PATZ) that interacts with RNF4, a mediator of androgen receptor activity, and acts as a transcriptional repressor. PATZ cDNA was isolated through a two-hybrid interaction screening using the RING finger protein RNF4 as a bait. In vitro and in vivo interaction between RNF4 and PATZ was demonstrated by protein-protein affinity chromatography and coimmunoprecipitation experiments. Such interaction occurred through a small region of PATZ containing an AT-hook DNA binding domain. Immunofluorescence staining and confocal microscopy showed that PATZ localizes in distinct punctate nuclear regions and colocalizes with RNF4. Functional analysis was performed by cotransfection assays: PATZ acted as a transcriptional repressor, whereas its partner RNF4 behaved as a transcriptional activator. When both proteins were overexpressed a strong repression of the basal transcription was observed, indicating that the association of PATZ with RNF4 switches activation to repression. In addition, RNF4 was also found to associate with HMGI(Y), a chromatin-modeling factor containing AT-hook domains.Several RING finger proteins play a crucial role in the control of transcription. mel-18, RING1, and KRIP-1 proteins act as transcriptional repressors and/or interact with transcriptional repressors (1-4). The RING finger protein PML interacts with Sp1 and inhibits the Sp1-mediated transcriptional activity (5). Most of the human RING finger proteins are localized in the nucleus or both in the cytoplasm and the nucleus and are often involved in oncogenesis by interfering with the transcriptional machinery (1). Chimeric proteins containing RING finger domains such as RET/rfp (6), TIF1/B-Raf (T18) (7), and PML/RAR␣ (8) are generated by chromosomal translocations occurring in different human neoplasias. Other transcriptionrelated RING finger proteins have oncogenic (c-Cbl and Bmi-1) or tumor suppressor (BRCA-1 and mel-18) activity (1). It is believed that in most cases RING finger proteins participate in the formation of multimeric complexes.We have recently isolated a human RING finger gene (RNF4) that encodes a protein of 190 amino acids (9). RNF4 is expressed at low levels in several tissues with the exception of a very high expression in the testis. The mouse homolog of RNF4 is abundantly expressed in embryonic tissues from the earliest days after gestation and exhibits a ubiquitous pattern of expression. The human RNF4 gene is located at 4p16.3, a chromosome region associated with several genetic and neoplastic diseases, between the huntingtin (HD) and the fibroblast growth factor receptor 3 (FGFR3) genes. Recently, the rat homolog of RNF4 has been shown to associate with the DNA binding domain of the androgen receptor (10) and to enhance both steroid receptor-dependent and basal transcription, suggesting that RNF4 may act as a bridging factor between nuclear receptors and other transcriptional factors.To identify molecular partners of RNF4 we have perfor...
BackgroundThe release of LPS by bacteria stimulates both immune and specific epithelial cell types to release inflammatory mediators. It is known that LPS induces the release of IL-8 by intestinal mucosal cells. Because it is now emerging that bacteria may induce alteration of epigenetic patterns in host cells, we have investigated whether LPS-induced IL-8 activation in human intestinal epithelial cells involves changes of histone modifications and/or DNA methylation at IL-8 gene regulatory region.ResultsRT-PCR analysis showed that IL-8 mRNA levels rapidly increase after exposure of HT-29 cells to LPS. DNA demethylating agents had no effects on IL-8 expression, suggesting that DNA methylation was not involved in IL-8 gene regulation. Consistently we found that 5 CpG sites located around IL-8 transcription start site (-83, -7, +73, +119, +191) were unmethylated on both lower and upper strand either in LPS treated or in untreated HT-29 cells, as well as in normal intestinal mucosa.Conversely, pretreatment of HT-29 cells with deacetylase inhibitors strengthened the LPS-mediated IL-8 activation. Inhibitors of histone deacetylases could induce IL-8 mRNA expression also in the absence of LPS, suggesting that chromatin modifications could be involved in IL-8 gene regulation. Chromatin immunoprecipitation analyses showed that, concurrently with IL-8 activation, transient specific changes in H3 acetylation and H3K4, H3K9 and H3K27 methylation occurred at IL-8 gene promoter during LPS stimulation. Changes of H3-acetyl, H3K4me2 and H3K9me2 levels occurred early, transiently and corresponded to transcriptional activity, while changes of H3K27me3 levels at IL-8 gene occurred later and were long lasting.ConclusionThe results showed that specific chromatin modifications occurring at IL-8 gene, including histone H3 acetylation and methylation, mark LPS-mediated IL-8 activation in intestinal epithelial cells while it is unlikely that DNA methylation of IL-8 promoter is directly involved in IL-8 gene regulation in these cells.
Autism spectrum disorders (ASD) are a group of heterogeneous neurodevelopmental conditions characterized by impaired social interaction, and repetitive stereotyped behaviours. Interestingly, functional and inflammatory gastrointestinal diseases are often reported as a comorbidity in ASDs, indicating gut-brain axis as a novel emerging approach. Recently, a central role for peroxisome-proliferator activated receptor (PPAR)-α has been addressed in neurological functions, associated with the behaviour. Among endogenous lipids, palmitoylethanolamide (PEA), a PPAR-α agonist, has been extensively studied for its anti-inflammatory effects both at central and peripheral level. Based on this background, the aim of this study was to investigate the pharmacological effects of PEA on autistic-like behaviour of BTBR T+tf/J mice and to shed light on the contributing mechanisms. Our results showed that PEA reverted the altered behavioural phenotype of BTBR mice, and this effect was contingent to PPAR-α activation. Moreover, PEA was able to restore hippocampal BDNF signalling pathway, and improve mitochondrial dysfunction, both pathological aspects, known to be consistently associated with ASDs. Furthermore, PEA reduced the overall inflammatory state of BTBR mice, reducing the expression of pro-inflammatory cytokines at hippocampal, serum, and colonic level. The analysis of gut permeability and the expression of colonic tight junctions showed a reduction of leaky gut in PEA-treated BTBR mice. This finding together with PEA effect on gut microbiota composition suggests an involvement of microbiota-gut-brain axis. In conclusion, our results demonstrated a therapeutic potential of PEA in limiting ASD symptoms, through its pleiotropic mechanism of action, supporting neuroprotection, anti-inflammatory effects, and the modulation of gut-brain axis.
We have identified a human gene encoding a novel MBD2-interacting protein (MBDin) that contains an N-terminal GTP-binding site, a putative nuclear export signal (NES), and a C-terminal acidic region. MBDin cDNA was isolated through a two-hybrid interaction screening using the methyl-CpG-binding protein MBD2 as bait. The presence of the C-terminal 46-amino-acid region of MBD2 and both the presence of the acidic C-terminal 128-amino-acid region and the integrity of the GTP-binding site of MBDin were required for the interaction. Interaction between MBD2 and MBDin in mammalian cells was confirmed by immunoprecipitation experiments. Fluorescence imaging experiments demonstrated that MBDin mainly localizes in the cytoplasm but accumulates in the nucleus upon disruption of the NES or treatment with leptomycin B, an inhibitor of NES-mediated transport. We also found that MBDin partially colocalizes with MBD2 at foci of heavily methylated satellite DNA. An MBD2 deletion mutant lacking the C-terminal region maintained its subnuclear localization but failed to recruit MBDin at hypermethylated foci. Functional analyses demonstrated that MBDin relieves MBD2-mediated transcriptional repression both when Gal4 chimeric constructs and when in vitro-methylated promoter-reporter plasmids were used in transcriptional assays. Southern blotting and bisulfite analysis showed that transcriptional reactivation occurred without changes of the promoter methylation pattern. Our findings suggest the existence of factors that could be targeted on methylated DNA by methyl-CpG-binding proteins reactivating transcription even prior to demethylation.Addition of methyl groups mostly at the CpG dinucleotide represents the major epigenetic modification of eukaryotic genomes heritable by somatic cells after cell division. DNA methylation plays an essential role in mammalian development (24) and in different biological processes such as tissue-specific gene expression (40), X-chromosome inactivation (17), genomic imprinting (2, 33), and repression of transposable elements (46). Abnormal methylation is a cause of human genetic diseases, including ICF syndrome (16), and is involved in carcinogenic processes primarily through aberrant hypermethylation of tumor suppressors' promoter regions (12,21,22).Methylated DNA is generally associated with transcriptional silencing (6, 7, 32), but how DNA methylation silences gene expression is not well understood. Studies are now focusing on the different components of the DNA methylation system and particularly on the mechanisms by which methyl-CpG signal is targeted, read, and maintained. Recently, a family of five mammalian methyl-CpG-binding proteins (MeCP2, MBD1, MBD2, MBD3, and MBD4) has been found to be essential to interpret the methylation patterns and to mediate the biological consequences of DNA methylation (1, 15, 18). All methyl-binding proteins share a common structural stretch of 60 to 80 amino acids called the mCpG-binding domain (MBD) and, with the exception of MBD4 (19, 34), mediate transcription...
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