Cell-type specific epigenomic profiling of major brain cell types in a mouse model of AD-like neurodegeneration
Gwyneth Welch1, Jemmie Cheng1, Easwaran Ramamurthy3, Manolis Kellis2, Andreas Pfenning3, and Li-Huei Tsai1.
1The Picower Institute for Learning and Memory, Brain and Cognitive Sciences Department, Massachuesetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 2Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; 3School of Computer Science, Carnegie Mellon University, Pittsburgh, Pennsylvania, 15213, USA.
Understanding the molecular mechanisms driving Alzheimer's Disease (AD) has proven to be a formidable challenge due to the complexity of the brain, which is composed of diverse classes of glia and neurons. Recent findings reveal gene regulatory elements such as enhancers in specific cell types likely play an important role in AD. Therefore, a cell-type specific approach is needed to identify the dynamic molecular profiles of individual cell types deregulated during AD progression.
To address this shortcoming, we have developed a method for profiling the epigenomes of specific brain cell types. We show that fluorescence-activated nuclei sorting can accurately isolate different brain cell types and that these sorted populations can be used for downstream chromatin analyses. We used ChIP-seq to profile H3K27ac enrichment, an epigenomic mark for active promoters and enhancers, in neurons, microglia, astrocytes, and oligodendrocytes from the CKp25 mouse model of neurodegeneration. In microglia, we find that enrichment for H3K27ac peaks is associated with genes involved in immune activation and inflammatory response in both early and late stages of neurodegeneration. Furthermore, we provide evidence that inflammatory response may involve other cell types. Our datasets may prove useful for elucidating the gene regulatory network responsible for inflammation and other important regulatory pathways contributing to AD pathophysiology in distinct neuronal and glial populations.
Funding by NIH-RF1-6934799, Glenn Foundation for Medical Research, and Cure Alzheimer's Fund.