Broadly Accessible Technologies for Single-cell Joint Analysis of Transcriptome and Epigenome

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Abstract Histone modifications carry rich information of cellular memory and gene regulatory mechanisms. Single cell analysis of histone modification in conjunction with transcriptome could recover this critical layer of cell identity and help to dissect the cellular and molecular composition of complex tissues such as the brain. We recently developed an ultra-high throughput single cell multi-omics assay, Paired-Tag, that can jointly map transcriptome and histone modifications from up to a million single cells in parallel. In order to translate this novel technology to the marketplace and to advance the goals of the BRAIN initiative, we propose to optimize and further develop Paired-Tag to enable its broad use in the research community. Specifically, we will develop Paired-Tag kits to allow for general accessibility of the method in molecular biology laboratories. We will then carry out extensive field tests of the Paired-Tag kit in the laboratories of current BRAIN initiative investigators, and further improve it based on the feedbacks. Finally, we will adapt the Paired-Tag procedure to long-read sequencing technologies to enable high throughput detection of splicing isoforms in brain cells at single cell resolution. If successful, the proposed research would provide researchers with a powerful new tool for single cell transcriptomics and epigenomics analysis.