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Series GSE236123 Query DataSets for GSE236123
Status Public on Sep 07, 2023
Title Enhancer grammar of liver cell types and hepatocyte zonation states [cell_lines_ATAC]
Organisms Homo sapiens; Mus musculus
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary Cell type identity is encoded by gene regulatory networks (GRN), in which transcription factors (TFs) bind to enhancers to regulate target gene expression. In the mammalian liver, lineage TFs have been characterized for the main cell types, including hepatocytes. Hepatocytes cover a relatively broad cellular state space, as they differ significantly in their metabolic state, and function, depending on their position with respect to the central or portal vein in a liver lobule. It is unclear whether this spatially defined cellular state space, called zonation, is also governed by a well-defined gene regulatory code. To address this challenge, we have mapped enhancer-GRNs (eGRNs) across liver cell types at high resolution, using a combination of single-cell multi-omics, spatial omics, GRN inference, and deep learning. We found that zonated variation in gene expression in hepatocytes, liver sinusoidal endothelial cells and hepatocellular stellate cells corroborate cell state changes in transcription and chromatin accessibility with spatial transcriptomics. eGRN mapping suggests that zonation states in hepatocytes are driven by the repressors Tcf7l1 and Tbx3, that modulate the core hepatocyte GRN, controlled by Hnf4a, Cebpa, Hnf1a, Onecut1 and Foxa1, among others. To investigate how these TFs cooperate with cell type TFs, we performed an in vivo Massively Parallel Reporter Assay (MPRA) on 12,000 hepatocyte enhancers and used these data to train a hierarchical deep learning model (called DeepLiver) that exploits both enhancer accessibility and activity. DeepLiver confirms Cebpa, Onecut, Foxa1, Hnf1a and Hnf4a as drivers of enhancer specificity in hepatocytes; Tcf7l1/2 and Tbx3 as regulators of the zonation state; and Hnf4a, Hnf1a, AP-1 and Ets as activators. Finally, taking advantage of in silico mutagenesis predictions from DeepLiver and MPRA, we confirmed that the destruction of Tcf7l1/2 or Tbx3 motifs in zonated enhancers abrogates their zonation bias. Our study provides a multi-modal explanation of the regulatory code underlying hepatocyte identity and their zonation state, that can be exploited to engineer enhancers with desired activity levels and zonation patterns.
Overall design 10x single cell multiome on the mouse liver
Contributor(s) González-Blas CB, Aerts S
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Submission date Jun 29, 2023
Last update date Sep 08, 2023
Contact name Carmen Bravo Gonzalez-Blas
Organization name VIB-KU Leuven Center for Brain & Disease Research
Street address Herestraat 49
City Leuven
ZIP/Postal code 3000
Country Belgium
Platforms (2)
GPL30172 NextSeq 2000 (Mus musculus)
GPL30173 NextSeq 2000 (Homo sapiens)
Samples (3)
GSM7518533 Bulk ATAC-seq on HepG2
GSM7518534 Bulk ATAC-seq on Hepa16
GSM7518535 Bulk ATAC-seq on AML12
This SubSeries is part of SuperSeries:
GSE218472 Enhancer grammar of liver cell types and hepatocyte zonation states
BioProject PRJNA989092

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE236123_RAW.tar 2.1 Gb (http)(custom) TAR (of BW)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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