RESUMO
Environmental factors can change phenotypes in exposed individuals and offspring and involve the germline, likely via biological signals in the periphery that communicate with germ cells. Here, using a mouse model of paternal exposure to traumatic stress, we identify circulating factors involving peroxisome proliferator-activated receptor (PPAR) pathways in the effects of exposure to the germline. We show that exposure alters metabolic functions and pathways, particularly lipid-derived metabolites, in exposed fathers and their offspring. We collected data in a human cohort exposed to childhood trauma and observed similar metabolic alterations in circulation, suggesting conserved effects. Chronic injection of serum from trauma-exposed males into controls recapitulates metabolic phenotypes in the offspring. We identify lipid-activated nuclear receptors PPARs as potential mediators of the effects from father to offspring. Pharmacological PPAR activation in vivo reproduces metabolic dysfunctions in the offspring and grand-offspring of injected males and affects the sperm transcriptome in fathers and sons. In germ-like cells in vitro, both serum and PPAR agonist induce PPAR activation. Together, these results highlight the role of circulating factors as potential communication vectors between the periphery and the germline.
Assuntos
Células Germinativas/metabolismo , Exposição Paterna , Animais , Sangue , Epigênese Genética , Epigenômica , Pai , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenótipo , Reprodução/fisiologia , Espermatozoides , Transcriptoma , Ferimentos e LesõesRESUMO
Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.
Assuntos
Envelhecimento/patologia , Transtornos da Memória/complicações , Transtornos da Memória/genética , MicroRNAs/biossíntese , Degeneração Neural/complicações , Degeneração Neural/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteína Fosfatase 1/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Proteínas Smad/metabolismoRESUMO
5-hydroxymethylation (5-hmC) is an epigenetic modification on DNA that results from the conversion of 5-methylcytosine by Ten-Eleven Translocation (TET) proteins. 5-hmC is widely present in the brain and is subjected to dynamic regulation during development and upon neuronal activity. It was recently shown to be involved in memory processes but currently, little is known about how it is controlled in the brain during memory formation. Here, we show that Tet3 is selectively up-regulated by activity in hippocampal neurons in vitro, and after formation of fear memory in the hippocampus. This is accompanied by a decrease in miR-29b expression that, through complementary sequences, regulates the level of Tet3 by preferential binding to its 3'UTR. We newly reveal that SAM68, a nuclear RNA-binding protein known to regulate splicing, acts upstream of miR-29 by modulating its biogenesis. Together, these findings identify novel players in the adult brain necessary for the regulation of 5-hmC during memory formation.
Assuntos
5-Metilcitosina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Medo , Regulação da Expressão Gênica , Hipocampo/fisiologia , Memória , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Dioxigenases , Camundongos Endogâmicos C57BL , Proteínas de Ligação a RNA/metabolismoRESUMO
BACKGROUND: The DNA of rheumatoid arthritis synovial fibroblasts (RASF) is globally hypomethylated; this contributes to an aggressive behaviour. In an attempt to remethylate these cells, we supplemented with methyl donors. We investigated the possible interference of microRNAs (miRs). MATERIAL AND METHODS: RASF were treated with L-methionine or betaine. Transcripts of de novo methyltransferases (DNMTs) and miRs were measured by real-time PCR, and a transcription PCR array was performed. Levels of homocysteine, matrix metalloproteinase-1 (MMP-1) and global DNA methylation were determined. Transfection with lipofectamine was performed with specific pre-miRs and anti-miRs, such as miR29 and let7f. RESULTS: L-methionine was more efficient to increase DNA methylation than betaine. This was associated with a reduced expression of DNMT3A mRNA in betaine-treated RASF. Betaine increases the expression of miR29 in RASF which targets DNMT3A, thereby limiting the remethylation process. Nevertheless, betaine inhibited the expression of multiple transcription factors, decreased the release of MMP-1, biosynthesis of homocysteine and cell migration. CONCLUSION: Alterations in cellular miRs profiles, in particular the upregulation of miR29, which targets DNMT3A, may limit the efficiency of betaine if it is used as DNA remethylating agent. However, L-methionine also has similar impact on miR29 expression. On the other hand, betaine has multiple other beneficial effects on the activated phenotype of RASF; it is not excluded that the effect of betaine on DNMT3A is, at least in part, indirect. Clinical trials with betaine could be promising.
RESUMO
Memory formation is a complex cognitive function regulated by coordinated synaptic and nuclear processes in neurons. In mammals, it is controlled by multiple molecular activators and suppressors, including the key signalling regulator, protein phosphatase 1 (PP1). Here, we show that memory control by PP1 involves the miR-183/96/182 cluster and its selective regulation during memory formation. Inhibiting nuclear PP1 in the mouse brain, or training on an object recognition task similarly increases miR-183/96/182 expression in the hippocampus. Mimicking this increase by miR-183/96/182 overexpression enhances object memory, while knocking-down endogenous miR-183/96/182 impairs it. This effect involves the modulation of several plasticity-related genes, with HDAC9 identified as an important functional target. Further, PP1 controls miR-183/96/182 in a transcription-independent manner through the processing of their precursors. These findings provide novel evidence for a role of miRNAs in memory formation and suggest the implication of PP1 in miRNAs processing in the adult brain.
