RESUMEN
Temporal dynamics and mechanisms underlying epigenetic changes in Huntington's disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.
Asunto(s)
Envejecimiento , Ensamble y Desensamble de Cromatina/genética , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Huntington/genética , Enfermedades Neurodegenerativas/genética , Animales , Conducta Animal/fisiología , Cromatina/genética , Cuerpo Estriado/citología , Cuerpo Estriado/fisiopatología , Epigenómica/métodos , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica , Humanos , Proteína Huntingtina/genética , Enfermedad de Huntington/diagnóstico , Enfermedad de Huntington/fisiopatología , Ratones Endogámicos C57BL , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/metabolismo , Expansión de Repetición de Trinucleótido/genéticaRESUMEN
Type 2 diabetes affects over 300 million people, causing severe complications and premature death, yet the underlying molecular mechanisms are largely unknown. Pancreatic islet dysfunction is central in type 2 diabetes pathogenesis, and understanding islet genome regulation could therefore provide valuable mechanistic insights. We have now mapped and examined the function of human islet cis-regulatory networks. We identify genomic sequences that are targeted by islet transcription factors to drive islet-specific gene activity and show that most such sequences reside in clusters of enhancers that form physical three-dimensional chromatin domains. We find that sequence variants associated with type 2 diabetes and fasting glycemia are enriched in these clustered islet enhancers and identify trait-associated variants that disrupt DNA binding and islet enhancer activity. Our studies illustrate how islet transcription factors interact functionally with the epigenome and provide systematic evidence that the dysregulation of islet enhancers is relevant to the mechanisms underlying type 2 diabetes.