Carmen Bravo González-Blas, Irina Matetovici, Hanne Hillen, Ibrahim Ihsan Taskiran, Roel Vandepoel et al.
In the mammalian liver, hepatocytes exhibit diverse metabolic and functional profiles based on their location within the liver lobule. However, it is unclear whether this spatial variation, called zonation, is governed by a well-defined gene regulatory code. Here, using a combination of single-cell multiomics, spatial omics, massively parallel reporter assays and deep learning, we mapped enhancer-gene regulatory networks across mouse liver cell types. We found that zonation affects gene expression and chromatin accessibility in hepatocytes, among other cell types. These states are driven by the repressors TCF7L1 and TBX3, alongside other core hepatocyte transcription factors, such as HNF4A, CEBPA, FOXA1 and ONECUT1. To examine the architecture of the enhancers driving these cell states, we trained a hierarchical deep learning model called DeepLiver. Our study provides a multimodal understanding of the regulatory code underlying hepatocyte identity and their zonation state that can be used to engineer enhancers with specific activity levels and zonation patterns.
Carmen Bravo González-Blas, Irina Matetovici, Hanne Hillen, Ibrahim Ihsan Taskiran, Roel Vandepoel, Valerie Christiaens, Leticia Sansores-García, Elisabeth Verboven, Gert Hulselmans, Suresh Poovathingal, Jonas Demeulemeester, Nikoleta Psatha, David Mauduit, Georg Halder, Stein Aerts. Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation. 2024-01-05. https://doi.org/10.1038/s41556-023-01316-4
Episomal 12K library testing accessible-region enhancer activity in mouse AML12 hepatocyte-like cells. This table summarizes two paired 5-prime AML12 cDNA/plasmid samples from the later GSE236121 submission.
Variant-focused 455-library MPRA in mouse liver with GFP-positive hepatocytes sorted by ECAD/CD73-associated zonation bins. This table summarizes five released FACS cDNA groups and normalizes them against the three matched bulk mouse plasmid references.
Episomal 12K library testing accessible-region enhancer activity in HepG2 cells. This table summarizes two paired 3-prime HepG2 cDNA/plasmid samples and carries the study's author activity calls and HepG2 effect statistics.
Episomal 12K library testing 10,845 accessible mouse hepatocyte regions with shuffled negatives and positive controls after hydrodynamic delivery. This table summarizes seven paired in vivo mouse liver cDNA/plasmid samples across the 5-prime and 3-prime barcode versions.
Variant-focused 455-library MPRA testing wild-type, motif perturbation, and gain-/loss-of-function enhancer constructs after in vivo delivery. This table summarizes eight bulk mouse cDNA samples against three shared plasmid DNA references at 48 h.
Variant-focused 455-library MPRA testing wild-type and engineered enhancer constructs in HepG2 cells. This table summarizes three paired HepG2 cDNA/plasmid samples at 48 h.
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
Download all 12 files (ZIP)GSE218470_Bulk_455_MPRA_counts.tsv.gzGSE218470_FACS_455_MPRA_counts.tsv.gzGSE218470_family.soft.gzGSE218471_12K_MPRA_counts.tsv.gzGSE218471_family.soft.gzGSE236121_AML12_MPRA_counts.tsv.gzGSE236121_family.soft.gzsource_data_extended_data.xlsxsource_data_fig3.xlsxsource_manifest.txtsupplementary_information.pdfsupplementary_tables.xlsx