Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem. Rehovot, Israel.
Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem. Rehovot, Israel.
J Nutr Biochem. 2023 Sep;119:109407. doi: 10.1016/j.jnutbio.2023.109407. Epub 2023 Jun 17.
Iron is essential to organism physiology as it participates in numerous biological processes including oxygen transport, respiration, and erythropoiesis. Although iron is critical to physiology, excess iron is toxic to cells and tissues due to generation of reactive oxygen species. Therefore, well-kept iron homeostasis is a mainstay of proper cell and organ function. Iron overload disorders, caused by nutritional or genetic factors, contribute to many pathologies such as diabetes, non-alcoholic steatohepatitis and hepatocellular carcinoma. The liver is not only vulnerable to the effects of iron overload, it is also the major organ controlling iron homeostasis. During iron overload, Bone Morphogenic Protein (BMP) levels increase and initiate a hepatic response aimed at lowering iron levels. The transcriptional effects of iron overload are not well-characterized and the underlining enhancer regulation is uncharted. Here, we profiled the liver's transcriptome and chromatin accessibility following nutritional iron overload. We found marked changes in gene expression and enhancer accessibility following iron overload. Surprisingly, 16% of genes induced following iron overload participate in propagating the cell cycle. Induction of cell cycle genes was independent of BMP. Genome-wide enhancer landscape profiling revealed hundreds of enhancers with altered activity following iron overload. Characterization of transcription factor motifs and footprints in iron-regulated enhancers showed a role for the Activator Protein 1 (AP-1) transcription factor in promoting cell cycle-related transcription. In summary, we found that the transcriptional program at play during iron overload is bifurcated in which BMP signaling controls iron homeostasis genes while an AP-1-driven program controls cell cycle genes.
铁是生物体生理学所必需的，因为它参与了许多生物过程，包括氧气运输、呼吸和红细胞生成。尽管铁对生理学至关重要，但由于活性氧的产生，过量的铁对细胞和组织是有毒的。因此，保持良好的铁平衡是适当的细胞和器官功能的主要支柱。由营养或遗传因素引起的铁过载疾病导致许多病理学，如糖尿病、非酒精性脂肪性肝炎和肝细胞癌。肝脏不仅容易受到铁过载的影响，而且还是控制铁平衡的主要器官。在铁过载时，骨形态发生蛋白（BMP）水平增加，并启动旨在降低铁水平的肝脏反应。铁过载的转录效应尚未很好地描述，其潜在的增强子调节也尚未被发现。在这里，我们对营养性铁过载后的肝脏转录组和染色质可及性进行了分析。我们发现铁过载后基因表达和增强子可及性发生了显著变化。令人惊讶的是，铁过载后诱导的 16%的基因参与了细胞周期的传播。细胞周期基因的诱导不依赖于 BMP。全基因组增强子景观分析显示，铁过载后数百个增强子的活性发生了改变。铁调节增强子中转录因子基序和足迹的特征表明，激活蛋白 1（AP-1）转录因子在促进与细胞周期相关的转录中发挥作用。总之，我们发现铁过载过程中的转录程序是分叉的，BMP 信号控制铁稳态基因，而 AP-1 驱动的程序控制细胞周期基因。
