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• W4312062050 abstract "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 across liver cell types at high resolution, using a combination of single cell multiomics, spatial omics, GRN inference, and deep learning. We found that cell state changes in transcription and chromatin accessibility in hepatocytes, liver sinusoidal endothelial cells and hepatic stellate cells depend on zonation. Enhancer-GRN 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 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 enhancer assays, we confirmed that the destruction of Tcf7l1/2 or Tbx3 motifs in zonated enhancers abrogates their zonation bias. Our study provides a multi-modal understanding of the regulatory code underlying hepatocyte identity and their zonation state, that can be exploited to engineer enhancers with specific activity levels and zonation patterns." @default.
• W4312062050 created "2023-01-04" @default.
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• W4312062050 date "2022-12-09" @default.
• W4312062050 modified "2023-10-18" @default.
• W4312062050 title "Enhancer grammar of liver cell types and hepatocyte zonation states" @default.
• W4312062050 cites W1508475810 @default.
• W4312062050 cites W1826646122 @default.
• W4312062050 cites W1979594866 @default.
• W4312062050 cites W1987176235 @default.
• W4312062050 cites W1989004527 @default.
• W4312062050 cites W1999430059 @default.
• W4312062050 cites W2001082470 @default.
• W4312062050 cites W2001896691 @default.
• W4312062050 cites W2003576907 @default.
• W4312062050 cites W2005081864 @default.
• W4312062050 cites W2007694108 @default.
• W4312062050 cites W2008047506 @default.
• W4312062050 cites W2010274889 @default.
• W4312062050 cites W2021093204 @default.
• W4312062050 cites W2032140335 @default.
• W4312062050 cites W2036897871 @default.
• W4312062050 cites W2038218774 @default.
• W4312062050 cites W2060568888 @default.
• W4312062050 cites W2062408930 @default.
• W4312062050 cites W2067956561 @default.
• W4312062050 cites W2084251771 @default.
• W4312062050 cites W2096128575 @default.
• W4312062050 cites W2108234281 @default.
• W4312062050 cites W2110905563 @default.
• W4312062050 cites W2115109074 @default.
• W4312062050 cites W2117757143 @default.
• W4312062050 cites W2128016314 @default.
• W4312062050 cites W2135782451 @default.
• W4312062050 cites W2145297900 @default.
• W4312062050 cites W2158789637 @default.
• W4312062050 cites W2160953907 @default.
• W4312062050 cites W2166691503 @default.
• W4312062050 cites W2170551349 @default.
• W4312062050 cites W2171808845 @default.
• W4312062050 cites W2178888844 @default.
• W4312062050 cites W2179438025 @default.
• W4312062050 cites W2181268165 @default.
• W4312062050 cites W2202976683 @default.
• W4312062050 cites W2278793656 @default.
• W4312062050 cites W2408306345 @default.
• W4312062050 cites W2529467427 @default.
• W4312062050 cites W2529838505 @default.
• W4312062050 cites W2553600202 @default.
• W4312062050 cites W2585175142 @default.
• W4312062050 cites W2633785026 @default.
• W4312062050 cites W2736547131 @default.
• W4312062050 cites W2750416916 @default.
• W4312062050 cites W2766459919 @default.
• W4312062050 cites W2768491523 @default.
• W4312062050 cites W2781473512 @default.
• W4312062050 cites W2781921089 @default.
• W4312062050 cites W2783975438 @default.
• W4312062050 cites W2789843538 @default.
• W4312062050 cites W2800392236 @default.
• W4312062050 cites W2806844404 @default.
• W4312062050 cites W2807884764 @default.
• W4312062050 cites W2809434958 @default.
• W4312062050 cites W2817838603 @default.
• W4312062050 cites W2898215009 @default.
• W4312062050 cites W2898598946 @default.
• W4312062050 cites W2932965638 @default.
• W4312062050 cites W2934716754 @default.
• W4312062050 cites W2942606873 @default.
• W4312062050 cites W2951764674 @default.
• W4312062050 cites W2951912016 @default.
• W4312062050 cites W2952481429 @default.
• W4312062050 cites W2953614989 @default.
• W4312062050 cites W2967059818 @default.
• W4312062050 cites W2972904585 @default.
• W4312062050 cites W2974173934 @default.
• W4312062050 cites W2981580264 @default.
• W4312062050 cites W2984472267 @default.
• W4312062050 cites W2989057263 @default.
• W4312062050 cites W2993816863 @default.
• W4312062050 cites W3006301383 @default.
• W4312062050 cites W3010018628 @default.
• W4312062050 cites W3023126733 @default.
• W4312062050 cites W3026792884 @default.
• W4312062050 cites W3045910546 @default.
• W4312062050 cites W3046345618 @default.

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