Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
Nat Immunol. 2023 Nov;24(11):1825-1838. doi: 10.1038/s41590-023-01631-w. Epub 2023 Sep 21.
Noncoding genetic variation drives phenotypic diversity, but underlying mechanisms and affected cell types are incompletely understood. Here, investigation of effects of natural genetic variation on the epigenomes and transcriptomes of Kupffer cells derived from inbred mouse strains identified strain-specific environmental factors influencing Kupffer cell phenotypes, including leptin signaling in Kupffer cells from a steatohepatitis-resistant strain. Cell-autonomous and non-cell-autonomous effects of genetic variation were resolved by analysis of F1 hybrid mice and cells engrafted into an immunodeficient host. During homeostasis, non-cell-autonomous trans effects of genetic variation dominated control of Kupffer cells, while strain-specific responses to acute lipopolysaccharide injection were dominated by actions of cis-acting effects modifying response elements for lineage-determining and signal-dependent transcription factors. These findings demonstrate that epigenetic landscapes report on trans effects of genetic variation and serve as a resource for deeper analyses into genetic control of transcription in Kupffer cells and macrophages in vitro.
非编码遗传变异驱动表型多样性，但潜在的机制和受影响的细胞类型仍不完全清楚。在这里，对来自近交系小鼠的库普弗细胞的表观基因组和转录组的自然遗传变异的影响进行研究，确定了影响库普弗细胞表型的特定于菌株的环境因素，包括来自脂肪性肝炎抗性菌株的库普弗细胞中的瘦素信号。通过分析 F1 杂种小鼠和移植到免疫缺陷宿主中的细胞，解决了遗传变异的细胞自主和非细胞自主效应。在体内平衡期间，遗传变异的非细胞自主转效应主导了对库普弗细胞的控制，而对急性脂多糖注射的特定于菌株的反应则主要由改变谱系决定和信号依赖性转录因子的反应元件的顺式作用效应的作用主导。这些发现表明，表观遗传景观报告了遗传变异的转效应，并可作为深入分析库普弗细胞和体外巨噬细胞中转录遗传控制的资源。
