Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Human Genetics Unit, Indian Statistical Institute, Kolkata, India.
Nat Struct Mol Biol. 2018 May;25(5):372-383. doi: 10.1038/s41594-018-0056-2. Epub 2018 Apr 23.
Iron metabolism is critical for sustaining life and maintaining human health. Here, we find that iron homeostasis is linked to facultative heterochromatin assembly and regulation of gene expression during adaptive genome control. We show that the fission yeast Clr4/Suv39h histone methyltransferase is part of a rheostat-like mechanism in which transcriptional upregulation of mRNAs in response to environmental change provides feedback to prevent their uncontrolled expression through heterochromatin assembly. Interestingly, proper iron homeostasis is required, as iron depletion or downregulation of iron transporters causes defects in heterochromatin assembly and unrestrained upregulation of gene expression. Remarkably, an unbiased genetic screen revealed that restoration of iron homeostasis is sufficient to re-establish facultative heterochromatin and proper gene control genome-wide. These results establish a role for iron homeostasis in facultative heterochromatin assembly and reveal a dynamic mechanism for reprogramming the genome in response to environmental changes.
铁代谢对于维持生命和人类健康至关重要。在这里，我们发现铁稳态与适应性基因组控制过程中的兼性异染色质组装和基因表达调控有关。我们表明，裂殖酵母 Clr4/Suv39h 组蛋白甲基转移酶是一种变阻器样机制的一部分，该机制通过转录上调 mRNA 来响应环境变化提供反馈，以防止通过异染色质组装失控表达。有趣的是，适当的铁稳态是必需的，因为铁耗竭或铁转运蛋白的下调会导致异染色质组装缺陷和基因表达不受控制的上调。值得注意的是，一项无偏遗传筛选揭示了铁稳态的恢复足以重新建立兼性异染色质和整个基因组的适当基因控制。这些结果确立了铁稳态在兼性异染色质组装中的作用，并揭示了一种针对环境变化重新编程基因组的动态机制。
