RESUMEN
Psychiatric diseases have a strong heritable component known to not be restricted to DNA sequence-based genetic inheritance alone but to also involve epigenetic factors in germ cells. Initial evidence suggested that sperm RNA is causally linked to the transmission of symptoms induced by traumatic experiences. Here, we show that alterations in long RNA in sperm contribute to the inheritance of specific trauma symptoms. Injection of long RNA fraction from sperm of males exposed to postnatal trauma recapitulates the effects on food intake, glucose response to insulin and risk-taking in adulthood whereas the small RNA fraction alters body weight and behavioural despair. Alterations in long RNA are maintained after fertilization, suggesting a direct link between sperm and embryo RNA.
Asunto(s)
Metilación de ADN , Epigénesis Genética , Metilación de ADN/genética , Epigénesis Genética/genética , Epigenómica , Masculino , ARN , Espermatozoides/metabolismoRESUMEN
Traumatic stress in early-life increases the risk for cognitive and neuropsychiatric disorders later in life. Such early stress can also impact the progeny even if not directly exposed, likely through epigenetic mechanisms. Here, we report in mice that the offspring of males subjected to postnatal traumatic stress have decreased gene expression in molecular pathways necessary for neuronal signaling, and altered synaptic plasticity when adult. Long-term potentiation is abolished and long-term depression is enhanced in the hippocampus, and these defects are associated with impaired long-term memory in both the exposed fathers and their offspring. The brain-specific gamma isoform of protein kinase C (Prkcc) is one of the affected signaling components in the hippocampus. Its expression is reduced in the offspring, and DNA methylation at its promoter is altered both in the hippocampus of the offspring and the sperm of fathers. These results suggest that postnatal traumatic stress in males can affect brain plasticity and cognitive functions in the adult progeny, possibly through epigenetic alterations in the male germline.
Asunto(s)
Encéfalo/patología , Trastornos del Conocimiento/etiología , Plasticidad Neuronal/fisiología , Trastornos de Estrés Traumático/complicaciones , Trastornos de Estrés Traumático/patología , Animales , Animales Recién Nacidos , Condicionamiento Psicológico , Metilación de ADN/genética , Epigénesis Genética , Miedo/psicología , Femenino , Expresión Génica , Hipocampo/citología , Técnicas In Vitro , Potenciación a Largo Plazo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa C/genética , Proteína Quinasa C/metabolismo , Reconocimiento en Psicología , Natación/psicologíaRESUMEN
Life experiences can induce epigenetic changes in mammalian germ cells, which can influence the developmental trajectory of the offspring and impact health and disease across generations. While this concept of epigenetic germline inheritance has long been met with skepticism, evidence in support of this route of information transfer is now overwhelming, and some key mechanisms underlying germline transmission of acquired information are emerging. This review focuses specifically on sperm RNAs as causal vectors of inheritance. We examine how they might become altered in the germline, and how different classes of sperm RNAs might interact with other epimodifications in germ cells or in the zygote. We integrate the latest findings with earlier pioneering work in this field, point out major questions and challenges, and suggest how new experiments could address them.
Asunto(s)
Mutación de Línea Germinal , Mamíferos/genética , Animales , Epigénesis Genética , Mutación de Línea Germinal/genética , Humanos , Patrón de Herencia , Masculino , ARN/genética , Espermatogénesis , Espermatozoides/fisiologíaRESUMEN
From fertilization throughout development and until death, cellular programs in individual cells are dynamically regulated to fulfill multiple functions ranging from cell lineage specification to adaptation to internal and external stimuli. Such regulation is of major importance in brain cells, because the brain continues to develop long after birth and incorporates information from the environment across life. When compromised, these regulatory mechanisms can have detrimental consequences on neurodevelopment and lead to severe brain pathologies and neurodegenerative diseases in the adult individual. Elucidating these processes is essential to better understand their implication in disease etiology. Because they are strongly influenced by environmental factors, they have been postulated to depend on epigenetic mechanisms. This review describes recent studies that have identified epigenetic dysfunctions in the pathophysiology of several neurodevelopmental and neurodegenerative diseases. It discusses currently known pathways and molecular targets implicated in pathologies including imprinting disorders, Rett syndrome, and Alzheimer's, Parkinson's and Hungtinton's disease, and their relevance to these diseases.