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<p>Pathogen-associated molecular patterns such as lipopolysaccharide (LPS) mimic immune responses triggered by bacterial infections. The hormonally active form of vitamin D<sub>3</sub>, 1α,25-dihydroxyvitamin&#xa0;D<sub>3</sub> [1,25(OH)<sub>2</sub>D<sub>3</sub>], 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&#xa0;h with 1,25(OH)<sub>2</sub>D<sub>3</sub> or LPS, followed by a second 24-hour stimulation with 1,25(OH)<sub>2</sub>D<sub>3</sub>, LPS, or their combination. Epigenome profiling <i>via</i> ATAC-seq revealed that co-stimulation with 1,25(OH)<sub>2</sub>D<sub>3</sub> 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 <i>via</i> RNA-seq mirrored these findings, though fewer genes than chromatin regions were affected. Notably, under 1,25(OH)<sub>2</sub>D<sub>3</sub>-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&#xa0;D modulates inflammation through epigenetic and transcriptional reprogramming.</p>

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Vitamin D and lipopolysaccharide jointly induce a distinct epigenetic and transcriptional program in human monocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • Mariusz Jankowski,
  • Emmi Hämäläinen,
  • Mari Taipale,
  • Sami Heikkinen,
  • Carsten Carlberg

摘要

Pathogen-associated molecular patterns such as lipopolysaccharide (LPS) mimic immune responses triggered by bacterial infections. The hormonally active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], 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)2D3 or LPS, followed by a second 24-hour stimulation with 1,25(OH)2D3, LPS, or their combination. Epigenome profiling via ATAC-seq revealed that co-stimulation with 1,25(OH)2D3 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)2D3-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.