Cell-Type-Specific Gene Expression Profiling in Adult Mouse Brain Reveals Normal and Disease-State Signatures

• Published in: Cell reports (Cambridge) Vol. 26; no. 9; pp. 2477 - 2493.e9
• Main Authors: Merienne, Nicolas, Meunier, Cécile, Schneider, Anne, Seguin, Jonathan, Nair, Satish S., Rocher, Anne B., Le Gras, Stéphanie, Keime, Céline, Faull, Richard, Pellerin, Luc, Chatton, Jean-Yves, Neri, Christian, Merienne, Karine, Déglon, Nicole
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.02.2019
• Subjects: Animals; Biochemistry, Molecular Biology; Brain - metabolism; cell-type-specific profiling; DNA - chemistry; Epigenesis, Genetic; epigenetics; Gene Expression Profiling - methods; Genomics; HD patients; HD transgenic mice; Humans; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington’s disease; Laser Capture Microdissection - methods; Life Sciences; Male; Mice; Mice, Transgenic; MicroRNAs - metabolism; Neurobiology; Neurons and Cognition; Nucleic Acid Conformation; RNA, Messenger - metabolism; striatum; Transcription Factors - metabolism; transcriptomics; HD transgenic mice; striatum; transcriptomics; cell-type-specific profiling; HD patients; Huntington’s disease; epigenetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.02.003

The role of brain cell-type-specific functions and profiles in pathological and non-pathological contexts is still poorly defined. Such cell-type-specific gene expression profiles in solid, adult tissues would benefit from approaches that avoid cellular stress during isolation. Here, we developed such an approach and identified highly selective transcriptomic signatures in adult mouse striatal direct and indirect spiny projection neurons, astrocytes, and microglia. Integrating transcriptomic and epigenetic data, we obtained a comprehensive model for cell-type-specific regulation of gene expression in the mouse striatum. A cross-analysis with transcriptomic and epigenomic data generated from mouse and human Huntington’s disease (HD) brains shows that opposite epigenetic mechanisms govern the transcriptional regulation of striatal neurons and glial cells and may contribute to pathogenic and compensatory mechanisms. Overall, these data validate this less stressful method for the investigation of cellular specificity in the adult mouse brain and demonstrate the potential of integrative studies using multiple databases. [Display omitted] •Optimized LCM method for mouse cell-type-specific dissection•Transcriptomic and network signatures of four adult striatal subpopulations•Role of transcription factors and DNA conformation in cell-type gene enrichment•Cell-type-specific contribution of epigenetic mechanisms in Huntington’ disease The contributions of neuronal and non-neuronal populations in cerebral functions are increasingly studied, but a robust and stress-limited method for cell-type-specific isolation is lacking. Merienne et al. optimize a laser-capture microdissection approach and characterize transcriptomic and epigenetic mechanisms in normal or pathological mouse and human Huntington’s disease (HD) brains.