Menin orchestrates macrophage reprogramming to maintain the pulmonary immune homeostasis [RNA-seq]

Menin is a scaffold protein encoded by the Men1 gene, and it interacts with a variety of chromatin regulators to activate or repress cellular processes. The potential importance of menin in immune regulation remains unclear. Here, we report that myeloid deletion of Men1 results in the development of spontaneous pulmonary alveolar proteinosis (PAP). This is strongly correlated with impaired development of alveolar macrophages (AM) and epigenetic inactivation of the GM-CSF pathway caused by Men1 deficiency. Mechanistically, menin directly interacts with SETD2 through the NTD and Palm domains to maintain protein stability and chromatin recruitment. SETD2 and menin collectively maintain GM-CSF expression through H3K36me3, which orchestrates AM reprogramming and pulmonary immune homeostasis. To explore the target genes of Men1 in macrophage, we isolated the alveolar macrophages from WT and Men1 knockout (KO) mice and performed gene expression profiling analysis by RNA-seq.Menin是由Men1基因编码的支架蛋白，可与多种染色质调控因子相互作用，激活或抑制细胞进程。其在免疫调控中的潜在重要性尚未明确。本研究发现，髓系细胞中Men1的缺失会引发自发性肺泡蛋白沉着症（pulmonary alveolar proteinosis, PAP），该表型与肺泡巨噬细胞（alveolar macrophages, AM）发育受损，以及Men1缺失导致的粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor, GM-CSF）通路表观遗传失活密切相关。机制研究显示，Menin可通过NTD结构域与Palm结构域直接与SETD2相互作用，以维持蛋白质稳定性与染色质招募能力。SETD2与Menin可共同通过H3K36me3维持GM-CSF的表达，进而调控肺泡巨噬细胞重编程与肺部免疫稳态。为探究巨噬细胞中Men1的靶基因，我们从野生型（wild-type, WT）和Men1敲除（knockout, KO）小鼠体内分离肺泡巨噬细胞，并通过RNA-seq开展基因表达谱分析。