Data Sheet 2_Multiomics profiles of genome-wide alterations in H3K27ac in different lung lobes after acute graft-versus-host disease with MSCs treatment.zip

The molecular characteristics of acute graft-versus-host disease (aGVHD) in different lung lobes and the treatment of aGVHD with mesenchymal stem cells are still poorly understood. In addition, despite the important role of acetylation on lysine 27 of histone H3 (H3K27ac) in the inflammatory response, little is known about genome-wide H3K27ac in GVHD and MSC treatment. In this study, we described 55 paired transcriptomes and genome-wide H3K27ac in five lung lobes, with groups designated as follows: control, GVHD, human placenta-derived MSC (hPMSC)-treated, and PBS-treated groups. We observed that inflammatory pathways were upregulated in GVHD but downregulated in hPMSCs. One algorithm was designed to identify the genes implicated in the prevention of GVHD by hPMSCs (the Rein02 gene), shedding light on a gene set with 892 Rein02 genes that are shared by all lobes and enriched in inflammatory pathways such as TNF-α signaling via NF-κb. The genome-wide H3K27ac data revealed lobe-specific patterns in the lobe behind the heart (H) and the left lobe (L) in the control and hPMSC groups, whereas these patterns were confused in the GVHD and PBS groups. Gene set enrichment analysis revealed that the hPMSC-induced variations in genome-wide H3K27ac were concentrated in the L and R3 lobes. The genes showing accordant tendencies (a-DEGs) between the transcriptome and H3K27ac highly overlapped between the a-DEGs and the Rein02 genes when hPMSCs were compared with GVHD. Integrated multiomics analysis suggested that the a-DEGs were predominantly expressed on myeloid (Fam174a, Ifi204, Slc7a11, Chil3, Capza2, Clec5a, and Clec4a2), T and NK cells (Eif3f, Cited2, Crybg1, Ndufs4, and Emb), B cells (Fam174a, Eif3f, and Blnk), and epithelial cells (Alcam, Chmp2b, and Metap2). The subset with high expression levels of these genes tended to present anti-inflammatory effects and reduced cytotoxic activity. Our study may provide new insights into the development of potential therapeutic drugs that target H3K27ac to assist in MSC treatment.

目前，关于不同肺叶急性移植物抗宿主病（acute graft-versus-host disease, aGVHD）的分子特征，以及间充质干细胞治疗aGVHD的相关机制仍不甚明确。此外，尽管组蛋白H3赖氨酸27乙酰化（histone H3 lysine 27 acetylation, H3K27ac）在炎症反应中发挥重要作用，但目前对于GVHD全基因组水平的H3K27ac修饰，以及间充质干细胞治疗后的H3K27ac变化仍知之甚少。本研究共纳入55对转录组与全基因组H3K27ac测序数据，样本来自5个肺叶，分为四组：对照组、GVHD模型组、人胎盘源间充质干细胞（human placenta-derived MSC, hPMSC）治疗组与磷酸盐缓冲液（phosphate buffered saline, PBS）对照组。研究发现，GVHD模型组的炎症通路显著上调，而hPMSC治疗组则呈现炎症通路下调趋势。本研究设计了一种算法，用于筛选hPMSC防治GVHD的核心基因（命名为Rein02基因），最终得到包含892个Rein02基因的基因集，该基因集在所有肺叶中均存在，且显著富集于TNF-α经NF-κB信号通路等炎症相关通路。全基因组H3K27ac测序数据显示，对照组与hPMSC治疗组中，心脏后方肺叶（H）与左肺叶（L）呈现肺叶特异性的H3K27ac修饰模式，而GVHD模型组与PBS对照组的该修饰模式则出现紊乱。基因集富集分析表明，hPMSC诱导的全基因组H3K27ac变化主要集中在L肺叶与R3肺叶。当比较hPMSC治疗组与GVHD模型组时，转录组与H3K27ac修饰趋势一致的差异表达基因（a-DEGs）与Rein02基因集存在高度重叠。整合多组学分析显示，这些a-DEGs主要在髓系细胞（Fam174a、Ifi204、Slc7a11、Chil3、Capza2、Clec5a及Clec4a2）、T细胞与自然杀伤细胞（Eif3f、Cited2、Crybg1、Ndufs4及Emb）、B细胞（Fam174a、Eif3f及Blnk）以及上皮细胞（Alcam、Chmp2b及Metap2）中高表达。高表达这些基因的细胞亚群往往呈现抗炎效应，并表现出细胞毒性活性降低的表型。本研究可为靶向H3K27ac的辅助间充质干细胞治疗相关潜在治疗药物的开发提供新的研究思路。