Jankowski Mariusz, Hämäläinen Emmi, Taipale Mari, Heikkinen Sami, Carlberg Carsten
Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, ul. Trylińskiego 18, Olsztyn, 10-683, Poland.
Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Sci Rep. 2025 Jul 28;15(1):27480. doi: 10.1038/s41598-025-10921-2.
Pathogen-associated molecular patterns such as lipopolysaccharide (LPS) mimic immune responses triggered by bacterial infections. The hormonally active form of vitamin D, 1α,25-dihydroxyvitamin D [1,25(OH)D], supports innate immunity, but its molecular mechanisms remain incompletely understood. We investigated epigenomic and transcriptomic changes in THP-1 monocytes that were either unprimed or primed for 24 h with 1,25(OH)D or LPS, followed by a second 24-hour stimulation with 1,25(OH)D, LPS, or their combination. Epigenome profiling via ATAC-seq revealed that co-stimulation with 1,25(OH)D and LPS induces substantially more chromatin accessibility changes than either treatment alone, with up to 81% of altered regions uniquely responsive to the combination. Motif enrichment analysis highlighted JUN/FOS transcription factors as key regulators of this synergistic response. Transcriptomic analysis via RNA-seq mirrored these findings, though fewer genes than chromatin regions were affected. Notably, under 1,25(OH)D-primed conditions, 331 genes exhibited synergistic expression changes upon co-treatment, meaning that their responses significantly deviates from the additive effects of the individual stimulations. This includes 264 genes previously unrecognized as vitamin D targets. Functional annotation revealed that these genes are primarily linked to monocyte and T cell differentiation, in contrast to classical vitamin D targets associated with inflammation. In conclusion, our findings provide mechanistic insight into how vitamin D modulates inflammation through epigenetic and transcriptional reprogramming.
病原体相关分子模式，如脂多糖（LPS），可模拟细菌感染引发的免疫反应。维生素D的激素活性形式，即1α,25-二羟基维生素D [1,25(OH)D]，可支持先天免疫，但其分子机制仍未完全阐明。我们研究了THP-1单核细胞的表观基因组和转录组变化，这些细胞要么未被激活，要么用1,25(OH)D或LPS预激活24小时，随后再用1,25(OH)D、LPS或它们的组合进行第二次24小时刺激。通过ATAC-seq进行的表观基因组分析表明，与单独使用任何一种处理相比，1,25(OH)D和LPS共同刺激诱导的染色质可及性变化显著更多，高达81%的改变区域对这种组合具有独特的反应。基序富集分析突出了JUN/FOS转录因子是这种协同反应的关键调节因子。通过RNA-seq进行的转录组分析反映了这些发现，尽管受影响的基因比染色质区域少。值得注意的是，在1,25(OH)D预激活的条件下，331个基因在联合处理时表现出协同表达变化，这意味着它们的反应明显偏离了单个刺激的累加效应。这包括264个以前未被识别为维生素D靶点的基因。功能注释显示，这些基因主要与单核细胞和T细胞分化有关，这与与炎症相关的经典维生素D靶点形成对比。总之，我们的研究结果为维生素D如何通过表观遗传和转录重编程调节炎症提供了机制性见解。
