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Abstract

Gene expression and chromatin accessibility are highly interconnected processes. Disentangling one without the other provides an incomplete picture of gene regulation. However, simultaneous measurements of RNA and accessible chromatin are technically challenging, especially when studying complex organs with rare cell-types. Here, we present easySHARE-seq, an elaboration of SHARE-seq, providing simultaneous measurements of ATAC- and RNA-seq within single cells, enabling identification of cell-type specific cis-regulatory elements (CREs). easySHARE-seq retains high scalability, improves RNA-seq data quality while also allowing for flexible study design. Using 19,664 joint profiles from murine liver nuclei, we linked CREs to their target genes and uncovered complex regulation of key genes such as Gata4. We further identify de-novo genes and cis-regulatory elements displaying zonation in Liver sinusoidal epithelial cells (LSECs), a challenging cell type with low mRNA levels, demonstrating the power of multimodal measurements. EasySHARE-seq therefore provides a flexible platform for investigating gene regulation across cell types and scale.