HyDrop v2: Scalable atlas construction for training sequence-to-function models

Deciphering cis-regulatory logic underlying cell type identity is a fundamental question in biology. Single-cell chromatin accessibility (scATAC-seq) data has enabled training of sequence-to-function deep learning models allowing decoding of enhancer logic and design of synthetic enhancers. Training such models requires large amounts of high-quality training data across species, organs, development, aging, and disease. To facilitate the cost-effective generation of large scATAC-seq atlases for model training, we developed a new version of the open-source microfluidic system HyDrop with increased sensitivity and scale: HyDrop v2. We generated HyDrop-v2 atlases for the mouse cortex and Drosophila embryo development and compared them to atlases generated on commercial platforms. HyDrop-v2 data integrates seamlessly with commercially available chromatin accessibility methods (10x Genomics). Differentially accessible regions and motif enrichment across cell types are equivalent between HyDrop-v2 and 10x atlases. Sequence-to-function models trained on either atlas are comparable as well in terms of enhancer predictions, sequence explainability, and transcription factor footprinting. By offering accessible data generation, enhancer models trained on HyDrop-v2 and mixed atlases can contribute to unraveling cell-type specific regulatory elements in health and disease. Overall design: singe-nucleus ATAC profiling of frozen mouse cortex tissue from adult BL/6Jax. The nuclei were dissociated and barcoded with different single-cell platforms and chemistries: 10x v1, 10x v2, HyDrop v1 and HyDrop v2. single-nucleus ATAC profiling of whole Drosohila melaogaster embryo of developmental stage 17. The embryos were collected at age 16 to 20h old, dechorionated and the nuclei lysed to be processed with different single-cell plattforms: 10x v2 and HyDrop v2. single-nucleus ATAC profiling of mixed samples (which ones) of cell lines as barnyard. The cells where lysed and barcoding was performed with single-cell platform HyDrop v2.