美国国立卫生研究院John J. OShea等合作取得一项新成果。他们的研究发现Il4-Il13-Il5位点的重塑是选择性基因表达的基础。相关论文于2024年11月20日发表于国际顶尖学术期刊《自然—免疫学》杂志上。

研究人员表示，II型细胞因子，包括白介素（IL）-4、IL-13和IL-5，位于一个多基因簇内。先天性淋巴细胞2型（ILC2）和适应性辅助性T细胞2型（TH2）都分泌II型细胞因子，但其分泌谱具有多样性。

利用转录因子足迹和染色质可及性，该研究组系统地对小鼠扩展的Il4-Il13-Il5位点上的调控元件（REs）进行了分类，分别为SHS-I/II、KHS-I/II、+6.5kbIl13、5HS-I（a,b,c,d,e）、5HS-II和5HS-III（a,b,c）。细胞活化后，调控元件之间的物理距离在三维空间中被协调重塑，导致Il4、Il13和Il5在不同re组合下的区隔分化。

调控元件的缺失表明，在体内，没有单一的调控元件能够完全解释特定细胞因子的选择性调节。相反，各个调控元件（RE）以不同方式对RE和目标基因的正确基因组定位做出贡献。删除这些调控元件会导致细胞因子表达，和组织免疫反应的情境依赖性失调。因此，信号依赖性的三维结构重塑，是II型细胞因子基因座产生多样化细胞因子输出的基础。

附：英文原文

Title: Remodeling of Il4-Il13-Il5 locus underlies selective gene expression

Author: Nagashima, Hiroyuki, Shayne, Justin, Jiang, Kan, Petermann, Franziska, Pkowska, Aleksandra, Kanno, Yuka, OShea, John J.

Issue&Volume: 2024-11-20

Abstract: The type 2 cytokines, interleukin (IL)-4, IL-13 and IL-5 reside within a multigene cluster. Both innate (ILC2) and adaptive T helper 2 (TH2) lymphocytes secrete type 2 cytokines with diverse production spectra. Using transcription factor footprint and chromatin accessibility, we systemically cataloged regulatory elements (REs) denoted as SHS-I/II, KHS-I/II, +6.5kbIl13, 5HS-I(a, b, c, d, e), 5HS-II and 5HS-III(a, b, c) across the extended Il4-Il13-Il5 locus in mice. Physical proximities among REs were coordinately remodeled in three-dimensional space after cell activation, leading to divergent compartmentalization of Il4, Il13 and Il5 with varied combinations of REs. Deletions of REs revealed no single RE solely accounted for selective regulation of a given cytokine in vivo. Instead, individual RE differentially contribute to proper genomic positioning of REs and target genes. RE deletions resulted in context-dependent dysregulation of cytokine expression and immune response in tissue. Thus, signal-dependent remodeling of three-dimensional configuration underlies divergent cytokine outputs from the type 2 loci.

DOI: 10.1038/s41590-024-02007-4

Source: https://www.nature.com/articles/s41590-024-02007-4