ISWI介导的核小体相位对髓系谱系稳态及刺激应答的调控，这一成果由欧洲肿瘤研究所Gioacchino Natoli团队经过不懈努力而取得。2025年9月25日，国际知名学术期刊《免疫学》发表了这一成果。

研究小组研究了核小体间距的关键调节因子ISWI染色质重塑因子的模仿对巨噬细胞分化和激活的影响，以及骨髓细胞中唯一的ISWI ATP酶SMARCA5的聚焦。骨髓源性巨噬细胞中条件性Smarca5的缺失破坏了PU.1结合位点附近的核小体分期，PU.1是骨髓特性所必需的先导TF，但不改变PU.1的占用。

然而，SMARCA5的缺失增加了C/EBPβ结合基序的可及性，这是一种弱先导TF，能够结合到非造血谱系中活跃的调控区域和引导谱系不适当的转录。这些变化还增加了刺激诱导的TF结合位点的可及性，导致巨噬细胞过度活化和刺激不适宜基因的错误表达。因此，SMARCA5依赖的核小体相位抑制C/EBPβ并刺激它们诱导的TF结合，确保巨噬细胞谱系规范和激活过程中的转录保真度，在其他免疫细胞类型中可能具有类似的作用。

据悉，染色质重塑子和先驱转录因子（TFs）之间的相互作用调节顺式调控元件的可及性，以维持细胞身份和转录保真度。

附：英文原文

Title: Control of myeloid lineage fidelity and response to stimuli by ISWI-enforced nucleosome phasing

Author: Sara Polletti, Júlia Melià-Alomà, Francesco Pileri, Chiara Anna Di Lena, Viviana Piccolo, Alessandro Cuomo, Tomas Stopka, Francesco Gualdrini, Gioacchino Natoli

Issue&Volume: 2025-09-25

Abstract: The interplay between chromatin remodelers and pioneer transcription factors (TFs) regulates cis-regulatory element accessibility to maintain cell identity and transcriptional fidelity. We investigated the impact of imitation of switch (ISWI) chromatin remodelers, key regulators of nucleosome spacing, on macrophage differentiation and activation, focusing on SMARCA5, the sole ISWI ATPase in myeloid cells. Conditional Smarca5 deletion in bone marrow-derived macrophages disrupted nucleosome phasing near sites bound by PU.1, a pioneer TF essential for myeloid identity, without altering PU.1 occupancy. However, SMARCA5 loss increased accessibility at motifs bound by C/EBPβ, a weak pioneer TF, enabling binding to regulatory regions active in non-hematopoietic lineages and causing lineage-inappropriate transcription. These changes also increased accessibility at sites bound by stimulus-induced TFs, leading to macrophage hyperactivation and mis-expression of stimulus-inappropriate genes. Thus, SMARCA5-dependent nucleosome phasing restrains C/EBPβ and stimulus-induced TF binding, ensuring transcriptional fidelity during macrophage lineage specification and activation, with likely similar roles in other immune cell types.

DOI: 10.1016/j.immuni.2025.09.002

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00413-3