美国加州大学Christopher K. Glass研究组揭示自然遗传变异对Kupffer细胞表观基因组和转录组的细胞内在和环境依赖效应的区分。这一研究成果发表在2023年9月21日出版的国际学术期刊《自然—免疫学》上。

自然遗传变异对来自近交小鼠品系的Kupffer细胞的表观基因组和转录组的影响进行了研究，发现了影响Kupffer细胞表型的品系特异性环境因素，包括来自脂肪性肝炎抗性品系的Kupffer细胞中的瘦素信号。通过分析F1杂交小鼠和移植到免疫缺陷宿主的细胞，解决了遗传变异的细胞自主和非细胞自主效应。

在稳态过程中，遗传变异的非细胞自主反式效应主导了Kupffer细胞的控制，而品系对急性脂多糖注射的特异性反应主要是由顺式作用作用修饰谱系决定因子和信号依赖性转录因子的反应元件的作用主导的。这些发现表明，表观遗传景观报告了遗传变异的反效应，并为深入分析体外库普弗细胞和巨噬细胞转录的遗传控制提供了资源。

据悉，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尚不完全清楚。

附：英文原文

Title: Discrimination of cell-intrinsic and environment-dependent effects of natural genetic variation on Kupffer cell epigenomes and transcriptomes

Author: Bennett, Hunter, Troutman, Ty D., Zhou, Enchen, Spann, Nathanael J., Link, Verena M., Seidman, Jason S., Nickl, Christian K., Abe, Yohei, Sakai, Mashito, Pasillas, Martina P., Marlman, Justin M., Guzman, Carlos, Hosseini, Mojgan, Schnabl, Bernd, Glass, Christopher K.

Issue&Volume: 2023-09-21

Abstract: 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.

DOI: 10.1038/s41590-023-01631-w

Source: https://www.nature.com/articles/s41590-023-01631-w