比利时鲁汶大学Stein Aerts团队报道，单细胞空间多组学和深度学习剖析肝脏分区中增强子驱动的基因调控网络。这一研究成果于2024年1月5日在线发表在国际学术期刊《自然—细胞生物学》上。

研究人员结合使用单细胞多组学、空间多组学、大规模并行报告测定和深度学习，绘制了小鼠肝细胞类型中的增强子-基因调控网络。研究人员发现，分区会影响肝细胞和其他细胞类型的基因表达和染色质可及性。这些状态由抑制因子TCF7L1和TBX3以及其他核心肝细胞转录因子（如HNF4A、CEBPA、FOXA1和ONECUT1）驱动。

为了研究驱动这些细胞状态的增强子的结构，研究人员训练了一个名为DeepLiver的分层深度学习模型。这项研究提供了对肝细胞特性及其分区状态的基础调控代码的多模式理解，并可用于设计具有特定活性水平和分区模式的增强子。

据了解，在哺乳动物肝脏中，肝细胞根据其在肝小叶中的位置而表现出不同的代谢和功能特征。然而，目前还不清楚这种被称为分区的空间变化是否受明确的基因调控代码支配。

附：英文原文

Title: Single-cell spatial multi-omics and deep learning dissect enhancer-driven gene regulatory networks in liver zonation

Author: Bravo Gonzlez-Blas, Carmen, Matetovici, Irina, Hillen, Hanne, Taskiran, Ibrahim Ihsan, Vandepoel, Roel, Christiaens, Valerie, Sansores-Garca, Leticia, Verboven, Elisabeth, Hulselmans, Gert, Poovathingal, Suresh, Demeulemeester, Jonas, Psatha, Nikoleta, Mauduit, David, Halder, Georg, Aerts, Stein

Issue&Volume: 2024-01-05

Abstract: 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.

DOI: 10.1038/s41556-023-01316-4

Source: https://www.nature.com/articles/s41556-023-01316-4