RESUMEN
Post-transcriptional RNA modifications have been recognized as key regulators of neuronal differentiation and synapse development in the mammalian brain. While distinct sets of 5-methylcytosine (m5C) modified mRNAs have been detected in neuronal cells and brain tissues, no study has been performed to characterize methylated mRNA profiles in the developing brain. Here, together with regular RNA-seq, we performed transcriptome-wide bisulfite sequencing to compare RNA cytosine methylation patterns in neural stem cells (NSCs), cortical neuronal cultures, and brain tissues at three postnatal stages. Among 501 m5C sites identified, approximately 6% are consistently methylated across all five conditions. Compared to m5C sites identified in NSCs, 96% of them were hypermethylated in neurons and enriched for genes involved in positive transcriptional regulation and axon extension. In addition, brains at the early postnatal stage demonstrated substantial changes in both RNA cytosine methylation and gene expression of RNA cytosine methylation readers, writers, and erasers. Furthermore, differentially methylated transcripts were significantly enriched for genes regulating synaptic plasticity. Altogether, this study provides a brain epitranscriptomic dataset as a new resource and lays the foundation for further investigations into the role of RNA cytosine methylation during brain development.
Asunto(s)
Metilación de ADN , ARN , Animales , ARN/metabolismo , ARN Mensajero/metabolismo , Citosina/metabolismo , Encéfalo/metabolismo , Transcriptoma , Mamíferos/genéticaRESUMEN
BACKGROUND: Folate is an essential B-group vitamin and a key methyl donor with important biological functions including DNA methylation regulation. Normal neurodevelopment and physiology are sensitive to the cellular folate levels. Either deficiency or excess of folate may lead to neurological disorders. Recently, folate has been linked to tRNA cytosine-5 methylation (m5C) and translation in mammalian mitochondria. However, the influence of folate intake on neuronal mRNA m5C modification and translation remains largely unknown. Here, we provide transcriptome-wide landscapes of m5C modification in poly(A)-enriched RNAs together with mRNA transcription and translation profiles for mouse neural stem cells (NSCs) cultured in three different concentrations of folate. RESULTS: NSCs cultured in three different concentrations of folate showed distinct mRNA methylation profiles. Despite uncovering only a few differentially expressed genes, hundreds of differentially translated genes were identified in NSCs with folate deficiency or supplementation. The differentially translated genes induced by low folate are associated with cytoplasmic translation and mitochondrial function, while the differentially translated genes induced by high folate are associated with increased neural stem cell proliferation. Interestingly, compared to total mRNAs, polysome mRNAs contained high levels of m5C. Furthermore, an integrative analysis indicated a transcript-specific relationship between RNA m5C methylation and mRNA translation efficiency. CONCLUSIONS: Altogether, our study reports a transcriptome-wide influence of folate on mRNA m5C methylation and translation in NSCs and reveals a potential link between mRNA m5C methylation and mRNA translation.
Asunto(s)
Ácido Fólico , Células-Madre Neurales , Ratones , Animales , ARN , Células-Madre Neurales/metabolismo , Metilación de ADN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Mamíferos/genéticaRESUMEN
Our understanding of RNA modifications has been growing rapidly over the last decade. Epitranscriptomics has recently emerged as an exciting, new field for understanding the fundamental mechanisms underlying RNA modifications and their impact on gene expression. Among the over one hundred different kinds of RNA modifications, cytosine methylation in mRNA (5-mrC) is now recognized as an important epigenetic mark that modulates mRNA transportation, translation, and stability at the post-transcriptional level. Across plant and animal species, recent studies have revealed the roles of mRNA cytosine methylation in several fundamental biological processes. In mammals, genome-wide profiling has determined thousands of mRNA transcripts carrying the 5-mrC modification in a tissue specific manner. Here, we summarize the experimental techniques that were exploited to determine 5-mrC in mRNA and the computational procedures implemented for RNA bisulfite sequencing data analysis.
Asunto(s)
Epigenómica/métodos , Procesamiento Postranscripcional del ARN , Análisis de Secuencia de ARN/métodos , Programas Informáticos , 5-Metilcitosina/análisis , Animales , Humanos , Metilación , ARN Mensajero/química , ARN Mensajero/genéticaRESUMEN
BACKGROUND: Recent studies have shown that early growth response 2 (EGR2) is highly induced in activated T cells and regulates T cell functions. In normal C57BL/6 (B6) mice, deletion of EGR2 in lymphocytes results in the development of lupus-like systemic autoimmune disease, which implies indirectly an autoimmune protective role of EGR2. Conversely, increased EGR2 gene expression is suggested to link with high risk of human lupus. In the present studies we sought to clarify the expression and inflammation regulatory role of EGR2 in murine lupus T cells directly. RESULTS: We performed RT-qPCR analysis and found a significant increase of EGR2 mRNA expression in human lupus PBMCs and in CD4+ T cells from three different murine lupus models including MRL-lpr, B6-lpr, and B6.sle123 mice at diseased stage when compared to age-matched control MRL or B6 mice. By performing intracellular flow cytometry analysis, we found that EGR2 protein expression was significantly increased in resting lupus (either MRL-lpr or B6.sle123) CD4+ T cells when compared to CD4+ T cells from their respective non-autoimmune controls. However, there was no difference of EGR2 protein expression in anti-CD3 and anti-CD28 stimulated control and lupus CD4+ T cells since there was a stronger induction of EGR2 in activated control CD4+ T cells. EGR2 expression was significantly increased in MRL-lpr mice at an age when lupus is manifested. To understand further the function of elevated EGR2 in lupus CD4+ T cells, we inhibited EGR2 with a specific siRNA in vitro in splenocytes from MRL-lpr and control MRL mice at 15 weeks-of-age. We found that EGR2 inhibition significantly reduced IFNγ production in PMA and ionomycin activated MRL-lpr lupus CD4+ T cells, but not control MRL CD4+ T cells. We also found that inhibition of EGR2 in vitro suppressed the Th1 differentiation in both MRL and MRL-lpr naïve CD4+ T cells. CONCLUSIONS: EGR2 is highly upregulated in human and murine lupus cells. Our in vitro data suggest a positive role of EGR2 in the regulation of Th1 differentiation and IFNγ production in lupus effector CD4+ T cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Inflamación/metabolismo , Lupus Eritematoso Sistémico/metabolismo , Nefritis Lúpica/metabolismo , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Humanos , Inflamación/inmunología , Interferón gamma/metabolismo , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos MRL lpr , Ratones Noqueados , Regulación hacia ArribaRESUMEN
Embryonic stem cells (ESCs) consist of a population of self-renewing cells displaying extensive phenotypic and functional heterogeneity. Research towards the understanding of the epigenetic mechanisms underlying the heterogeneity among ESCs is still in its initial stage. Key issues, such as how to identify cell-subset specifically methylated loci and how to interpret the biological meanings of methylation variations remain largely unexplored. To fill in the research gap, we implemented a computational pipeline to analyze single-cell methylome and to perform an integrative analysis with single-cell transcriptome data. According to the origins of variation in DNA methylation, we determined the genomic loci associated with allelic-specific methylation or asymmetric DNA methylation, and explored a beta mixture model to infer the genomic loci exhibiting cell-subset specific methylation (CSM). We observed that the putative CSM loci in ESCs are significantly enriched in CpG island (CGI) shelves and regions with histone marks for promoter and enhancer, and the genes hosting putative CSM loci show wide-ranging expression among ESCs. More interestingly, the putative CSM loci may be clustered into co-methylated modules enriching the binding motifs of distinct sets of transcription factors. Taken together, our study provided a novel tool to explore single-cell methylome and transcriptome to reveal the underlying transcriptional regulatory networks associated with epigenetic heterogeneity of ESCs.
Asunto(s)
Epigenómica/métodos , Perfilación de la Expresión Génica/métodos , Análisis de la Célula Individual/métodos , Animales , Islas de CpG/fisiología , Metilación de ADN/fisiología , Bases de Datos Genéticas , Células Madre Embrionarias/metabolismo , Epigénesis Genética/genética , Redes Reguladoras de Genes/genética , Heterogeneidad Genética , Genómica , Ratones , Células Madre Embrionarias de Ratones/metabolismo , Regiones Promotoras Genéticas/genética , Factores de Transcripción/metabolismo , Transcriptoma/genéticaRESUMEN
Spectrum sensing is the most important task in cognitive radio (CR). In this paper, a new robust distributed spectrum sensing approach, called diffusion maximum correntropy criterion (DMCC)-based robust spectrum sensing, is proposed for CR in the presence of non-Gaussian noise or impulsive noise. The proposed distributed scheme, which does not need any central processing unit, is characterized by an adaptive diffusion model. The maximum correntropy criterion, which is insensitive to impulsive interference, is introduced to deal with the effect of non-Gaussian noise. Simulation results show that the DMCC-based spectrum sensing algorithm has an excellent robust property with respect to non-Gaussian noise. It is also observed that the new method displays a considerably better detection performance than its predecessor (i.e., diffusion least mean square (DLMS)) in impulsive noise. Moreover, the mean and variance convergence analysis of the proposed algorithm are also carried out.
RESUMEN
Subclinical super-low-dose endotoxin LPS is a risk factor for the establishment of low-grade inflammation during the pathogenesis and progression of chronic diseases. However, the underlying mechanisms are not well understood. At the cellular level, a disruption of lysosome fusion with endosomes or autophagosomes may contribute to the potentiation of low-grade inflammation. In this study, we identified that subclinical super-low-dose endotoxin LPS can potently inhibit the process of endosome acidification and lysosome fusion with endosomes or autophagosomes in primary macrophages. Super-low-dose LPS induced the inhibitory phosphorylation of VPS34, thus leading to the disruption of endosome-lysosome fusion. This effect may depend upon the clearance and relocation of Tollip in macrophages by super-low-dose LPS. Consistent with this notion, Tollip-deficient macrophages had constitutively elevated levels of VPS34 inhibitory phosphorylation and constitutive disruption of endosome-lysosome fusion. By employing a skin excision wound-healing model, we observed that Tollip-deficient mice had significantly elevated levels of cell stress and reduced wound repair. This study reveals a novel mechanism responsible for the modulation of endosome-lysosome fusion and low-grade inflammation in innate macrophages.
Asunto(s)
Autofagia/inmunología , Inmunidad Innata , Inflamación/inmunología , Lipopolisacáridos/toxicidad , Lisosomas/inmunología , Animales , Endosomas/efectos de los fármacos , Endosomas/inmunología , Humanos , Inflamación/inducido químicamente , Inflamación/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Lisosomas/efectos de los fármacos , Lisosomas/patología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: Glypican-3 (GPC3) is an oncofetal antigen that shows great promise as a biomarker for diagnosis of hepatocellular carcinoma (HCC), but there is no reliable kit that can be used to detect it in clinics. The aim of this study is to develop a stable performance kit for GPC3 detection in clinics. DESIGN AND METHODS: The paired antibodies were identified through cycle-screening methods based on our previous research. Then, a double antibodies sandwich chemiluminescent immunoassay for detecting serum GPC3 was developed. The performance of the developed GPC3 diagnostic kit was evaluated by detecting the concentration of serum GPC3 and assessing its single or combined use with alpha fetoprotein (AFP) and cytokeratin 19 fragment (CK19) for HCC diagnosis. RESULTS: The assay demonstrated a linear range of 10-800 ng/ml, the cross-reactivity rate at 0.018% (AFP), 0.020% (carcino-embryonic antigen), and 0.021% (CK19), respectively. The minimum detectable concentration was 0.05 ng/ml; the intraassay coefficient of variation (CV) and interassay CV were both less than 10%, with good stability and reproducibility. GPC3 has a high sensitivity (54.2%) and specificity (99.4%) in diagnosing HCC. The level of GPC3 in HCC was robust higher than that in healthy or other liver diseases' sera (108.67 ± 230.04 ng/ml vs. 3.99 ± 7.68 ng/ml). The diagnostic sensitivity of GPC3 single or combined with CK19 and AFP for HCC was evaluated, and the rates were 54.2 and 90.6%, respectively. CONCLUSIONS: An applicable chemiluminescent immunoassay with stable performance against GPC3 in diagnosing HCC has been established and the combination of GPC3 with CK19 and AFP could improve the diagnostic sensitivity for HCC.
Asunto(s)
Carcinoma Hepatocelular/sangre , Glipicanos/sangre , Queratina-19/sangre , Neoplasias Hepáticas/sangre , Mediciones Luminiscentes/métodos , alfa-Fetoproteínas/análisis , Biomarcadores de Tumor/sangre , Humanos , Inmunoensayo/métodos , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Defectos del Tubo Neural , Animales , Ratones , Humanos , Suplementos Dietéticos/efectos adversos , Ácido Fólico/uso terapéutico , Defectos del Tubo Neural/prevención & control , FamiliaRESUMEN
Folate, an essential vitamin B9, is crucial for diverse biological processes including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Here, we employed mouse model and spatial transcriptomics and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.
RESUMEN
Genes that regulate hormone release are essential for maintaining metabolism and energy balance. Egr1 encodes a transcription factor that regulates hormone production and release, and a decreased in growth hormones has been reported in Egr1 knockout mice. A reduction in growth hormones has also been observed in Nestin-Cre mice, a model frequently used to study the nervous system. Currently, it is unknown how Egr1 loss or the Nestin-Cre driver disrupt pituitary gene expression. Here, we compared the growth curves and pituitary gene expression profiles of Nestin-Cre-mediated Egr1 conditional knockout (Egr1cKO) mice with those of their controls. Reduced body weight was observed in both the Nestin-Cre and Egr1cKO mice, and the loss of Egr1 had a slightly more severe impact on female mice than on male mice. RNA-seq data analyses revealed that the sex-related differences were amplified in the Nestin-Cre-mediated Egr1 conditional knockout mice. Additionally, in the male mice, the influence of Egr1cKO on pituitary gene expression may be overridden by the Nestin-Cre driver. Differentially expressed genes associated with the Nestin-Cre driver were significantly enriched for genes related to growth factor activity and binding. Altogether, our results demonstrate that Nestin-Cre and the loss of Egr1 in the neuronal cell lineage have distinct impacts on pituitary gene expression in a sex-specific manner.
RESUMEN
The transcription factor EGR1 is instrumental in numerous neurological processes, encompassing learning and memory as well as the reaction to stress. Egr1 complete knockout mice demonstrate decreased depressive or anxiety-like behavior and impaired performance in spatial learning and memory. Nevertheless, the specific functions of Egr1 in distinct cell types have been largely underexplored. In this study, we cataloged the behavioral and transcriptomic character of Nestin-Cre mediated Egr1 conditional knockout (Egr1cKO) mice together with their controls. Although the conditional knockout did not change nociceptive or anxiety responses, it triggered changes in female exploratory activity during anxiety testing. Hippocampus-dependent spatial learning in the object location task was unaffected, but female Egr1cKO mice did exhibit poorer retention during testing on a contextual fear conditioning task compared to males. RNA-seq data analyses revealed that the presence of the floxed Egr1 cassette or Nestin-Cre driver alone exerts a subtle influence on hippocampal gene expression. The sex-related differences were amplified in Nestin-Cre mediated Egr1 conditional knockout mice and female mice are more sensitive to the loss of Egr1 gene. Differentially expressed genes resulted from the loss of Egr1 in neuronal cell lineage were significantly associated with the regulation of Wnt signaling pathway, extracellular matrix, and axon guidance. Altogether, our results demonstrate that Nestin-Cre and the loss of Egr1 in neuronal cell lineage have distinct impacts on hippocampal gene expression in a sex-specific manner.
RESUMEN
Neuronal activity is accomplished via substantial changes in gene expression, which may be accompanied by post-transcriptional modifications including RNA cytosine-5 methylation (m5C). Despite several reports on the transcriptome profiling of activated neurons, the dynamics of neuronal mRNA m5C modification in response to environmental stimuli has not been explored. Here, we provide transcriptome-wide maps of m5C modification, together with gene expression profiles, for mouse cortical neurons at 0 h, 2 h, and 6 h upon membrane depolarization. Thousands of differentially expressed genes (DEGs) were identified during the neuronal depolarization process. In stimulated neurons, the majority of early response genes were found to serve as expression regulators of late response genes, which are involved in signaling pathways and diverse synaptic functions. With RNA bisulfite sequencing data, a union set of 439 m5C sites was identified with high confidence, and approximately 30% of them were shared by neurons at all three time points. Interestingly, over 41% of the m5C sites showed increased methylation upon neuronal activation and were enriched in transcripts coding for proteins with synaptic functions. In addition, a modest negative correlation was observed between RNA expression and methylation. In summary, our study provided dynamic transcriptome-wide landscapes of RNA m5C methylation in neurons, and revealed that mRNA m5C methylation is associated with the regulation of gene expression.
RESUMEN
The presence of 5-methylcytosine (m5C) in RNA molecules has been known for decades and its importance in regulating RNA metabolism has gradually become appreciated. Despite recent advances made in the functional and mechanistic understanding of RNA m5C modifications, the detection and quantification of methylated RNA remains a challenge. In this study, we compared four library construction procedures for RNA bisulfite sequencing and implemented an analytical pipeline to assess the key parameters in the process of m5C calling. We found that RNA fragmentation after bisulfite conversion increased the yield significantly, and an additional high temperature treatment improved bisulfite conversion efficiency especially for sequence reads mapped to the mitochondrial transcriptome. Using Unique Molecular Identifiers (UMIs), we observed that PCR favors the amplification of unmethylated templates. The low sequencing quality of bisulfite-converted bases is a major contributor to the methylation artifacts. In addition, we found that mitochondrial transcripts are frequently resistant to bisulfite conversion and no p-m5C sites with high confidence could be identified on mitochondrial mRNAs. Taken together, this study reveals the various sources of artifacts in RNA bisulfite sequencing data and provides an improved experimental procedure together with analytical methodology.
RESUMEN
The epigenome, including DNA methylation, is stably propagated during mitotic division. However, single-cell clonal expansion produces heterogeneous methylomes, thus raising the question of how the DNA methylome remains stable despite constant epigenetic drift. Here, we report that a clonal population of DNA (cytosine-5)-methyltransferase 1 (DNMT1)-only cells produces a heterogeneous methylome, which is robustly propagated on cell expansion and differentiation. Our data show that DNMT1 has imprecise maintenance activity and possibly possesses weak de novo activity, leading to spontaneous 'epimutations'. However, these epimutations tend to be corrected through a neighbor-guided mechanism, which is likely to be enabled by the environment-sensitive de novo activity ('tuner') and maintenance activity ('stabilizer') of DNMT1. By generating base-resolution maps of de novo and maintenance activities, we find that H3K9me2/3-marked regions show enhanced de novo activity, and CpG islands have both poor maintenance and de novo activities. The imprecise epigenetic machinery coupled with neighbor-guided correction may be a fundamental mechanism underlying robust yet flexible epigenetic inheritance.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasa 1/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Herencia/genética , Animales , Células Cultivadas , Islas de CpG/genética , ADN/genética , Bases de Datos Genéticas , Epigenómica/métodos , RatonesRESUMEN
DNA methylation plays important roles in the regulation of nervous system development and in cellular responses to environmental stimuli such as light-derived signals. Despite great efforts in understanding the maturation and refinement of visual circuits, we lack a clear understanding of how changes in DNA methylation correlate with visual activity in the developing subcortical visual system, such as in the dorsal lateral geniculate nucleus (dLGN), the main retino-recipient region in the dorsal thalamus. Here, we explored epigenetic dynamics underlying dLGN development at ages before and after eye opening in wild-type mice and mutant mice in which retinal ganglion cells fail to form. We observed that development-related epigenetic changes tend to co-localize together on functional genomic regions critical for regulating gene expression, while retinal-input-induced epigenetic changes are enriched on repetitive elements. Enhancers identified in neurons are prone to methylation dynamics during development, and activity-induced enhancers are associated with retinal-input-induced epigenetic changes. Intriguingly, the binding motifs of activity-dependent transcription factors, including EGR1 and members of MEF2 family, are enriched in the genomic regions with epigenetic aberrations in dLGN tissues of mutant mice lacking retinal inputs. Overall, our study sheds new light on the epigenetic regulatory mechanisms underlying the role of retinal inputs on the development of mouse dLGN.
Asunto(s)
Epigénesis Genética , Cuerpos Geniculados/metabolismo , Retina/metabolismo , Animales , Metilación de ADN , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Cuerpos Geniculados/crecimiento & desarrollo , Factores de Transcripción MEF2/metabolismo , Ratones , Ratones Endogámicos C57BL , Unión Proteica , Retina/crecimiento & desarrollo , Vías Visuales/crecimiento & desarrollo , Vías Visuales/metabolismoRESUMEN
BACKGROUND: Numerous cell types can be identified within plant tissues and animal organs, and the epigenetic modifications underlying such enormous cellular heterogeneity are just beginning to be understood. It remains a challenge to infer cellular composition using DNA methylomes generated for mixed cell populations. Here, we propose a semi-reference-free procedure to perform virtual methylome dissection using the nonnegative matrix factorization (NMF) algorithm. RESULTS: In the pipeline that we implemented to predict cell-subtype percentages, putative cell-type-specific methylated (pCSM) loci were first determined according to their DNA methylation patterns in bulk methylomes and clustered into groups based on their correlations in methylation profiles. A representative set of pCSM loci was then chosen to decompose target methylomes into multiple latent DNA methylation components (LMCs). To test the performance of this pipeline, we made use of single-cell brain methylomes to create synthetic methylomes of known cell composition. Compared with highly variable CpG sites, pCSM loci achieved a higher prediction accuracy in the virtual methylome dissection of synthetic methylomes. In addition, pCSM loci were shown to be good predictors of the cell type of the sorted brain cells. The software package developed in this study is available in the GitHub repository (https://github.com/Gavin-Yinld). CONCLUSIONS: We anticipate that the pipeline implemented in this study will be an innovative and valuable tool for the decoding of cellular heterogeneity.
Asunto(s)
Metilación de ADN , Análisis de la Célula Individual/métodos , Algoritmos , Animales , Encéfalo/metabolismo , Islas de CpG , Sitios Genéticos , Ratones , Neuronas/citología , Neuronas/metabolismo , Análisis de Componente Principal , Interfaz Usuario-ComputadorRESUMEN
Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.
Asunto(s)
Encéfalo/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Epigenoma/fisiología , Neuronas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Animales , Sitios de Unión , Metilación de ADN , Proteínas de Unión al ADN/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Epigenoma/genética , Epigenómica , Regulación de la Expresión Génica , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Neurogénesis/fisiología , Plasticidad Neuronal/fisiología , Dominios y Motivos de Interacción de Proteínas , Proteínas Proto-Oncogénicas/genética , Factores de Transcripción , TranscriptomaRESUMEN
Short-term curative effect and safety of propranolol combined with laser in the treatment of infantile hemangiomas was studied, so as to provide reference for clinical treatment. A total of 100 cases of infantile hemangiomas admitted to the Affiliated Hospital of Jining Medical University from October 2014 to June 2016 were selected into this study. According to the random number table method, they were divided into the control group and the observation group, with 50 cases in each group. The infant patients in the control group were treated with laser alone, and the infant patients in the observation group were treated with propranolol combined with laser. The healing time, the number of times of laser therapy, the short-term curative effect, the changes in serum inflammatory factors before and after treatment and the incidence of adverse reactions were compared between the two groups of infant patients. The healing time and the times of laser therapy of the infant patients in the observation group were less than those of the infant patients in the control group, and the differences were statistically significant (p<0.05). The short-term curative effect of the observation group (98%) was higher than that of the control group (82%), and the difference was statistically significant (p<0.05). The levels of serum inflammatory factors interleukin (IL)-2, IL-6 and IL-10 in the two groups of infant patients after treatment were lower than those before treatment, and the levels in the observation group were lower than those in the control group, and the differences were statistically significant (p<0.05). Propranolol combined with laser in the treatment of infantile hemangiomas has remarkable short-term curative effects. It can effectively reduce the levels of inflammatory factors, shorten the healing time and reduce the number of times of laser therapy. It is safe and worthy of clinical promotion.
RESUMEN
RATIONALE: Ulcerative colitis (UC) is one of the chronic inflammatory diseases of the intestinal tract. UC being misdiagnosed as Henoch-Schönlein purpura (HSP) in the elderly has seldom been reported about. PATIENT CONCERNS: A 64-year-old man was admitted to the hospital with petechiae and palpable purpura in lower limbs and abdominal pain for about 1 month. DIAGNOSES: Colonoscopy demonstrated severe inflammation in the colon, mucosal congestion, and edema, and multiple hemorrhages and ulcerations, with purulent adhesions. A histopathologic examination of the colon biopsies revealed extensive infiltration of immune cells and mucosal ulcerations in the intestine. UC was diagnosed. INTERVENTIONS: The patient was treated with prednisone (1.0âmg/kg/d) with progressive dose reduction. OUTCOMES: The skin lesions were healed within 4 weeks, and his abdominal pain was alleviated remarkably. He is currently under follow-up. LESSONS: As the treatment used for patients with HSP was not effective, it was advised that UC should be taken into consideration.