Emerging Role of C/EBPβ and Epigenetic DNA Methylation in Ageing

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C/ebp 和表观遗传 DNA 甲基化在衰老中的作用

geing is closely associated with and influenced by energy metabolism, and C/EBPβ is emerging as a key regulator of energy metabolism and longevity.

DNA hypermethylation in GADD45α/ING1 mutant mice is associated with progeria due to a failure of TET-dioxygenase mediated demethylation of C/EBPβ binding sites.

Accordingly, GADD45α/ING1 mutant mice phenocopy major symptoms of C/EBPβ mutant mice, indicating that a GADD45α–ING1–C/EBPβ axis regulates energy metabolism and ageing.

mTORC1 controls the translation of Cebpb-mRNA into two isoforms, the transcriptional activator liver-enriched activating protein (LAP), and inhibitor liver-enriched inhibitory protein (LIP). C/EBPβ super-mice, in which the inhibitory LIP is inactivated display healthier ageing and prolonged life span.

The results indicate a causal nexus between C/EBPβ, energy metabolism, and DNA demethylation in organismal ageing.

衰老与能量代谢密切相关,并受能量代谢的影响,c/ebp 正在成为能量代谢和长寿的关键调节因子。Gadd45/ing1突变小鼠 DNA 高甲基化与 tet- 双加氧酶介导的 c/ebp 结合位点去甲基化失败导致的早衰有关。因此,gadd45/ING1突变小鼠表现出 c/ebp 突变小鼠的主要症状,提示 gadd45-ING1-c/ebp 轴调节能量代谢和衰老。mTORC1控制转录因子丰肝激活蛋白(LAP)和抑制剂丰肝抑制蛋白(LIP)两种亚型的转录。抑制性 LIP 失活的 c/ebp 超级小鼠衰老更健康,寿命更长。结果表明,c/ebp、能量代谢和 DNA 去甲基化在生物体衰老过程中存在因果关系。

Changes in epigenetic DNA methylation are the most promising predictor of biological age and lifespan in humans, but whether methylation changes affect ageing is unresolved. Here, we discuss converging data, which indicate that one mode by which aberrant DNA methylation can affect ageing is via CCAAT/enhancer binding protein beta (C/EBPβ). This basic leucine-zipper (bZIP) transcription factor is controlled by the lifespan regulator mechanistic/mammalian target of rapamycin complex 1 (mTORC1) and plays an important role in energy homeostasis and adipose tissue differentiation. Emerging evidence indicates that access of C/EBPβ proteins to cognate binding sites is regulated by DNA demethylation via ten-eleven translocation (TET) methylcytosine dioxygenases and their adaptor proteins growth arrest and DNA damage-inducible protein 45 alpha (GADD45α) and inhibitor of growth 1 (ING1). We discuss the emerging causal nexus between C/EBPβ, energy metabolism, and DNA demethylation in organismal ageing.

表观遗传 DNA 甲基化的变化是人类生物年龄和寿命最有前途的预测因子,但是甲基化变化是否影响衰老尚未解决。在这里,我们讨论汇聚的数据,这表明异常 DNA 甲基化可以影响衰老的一个模式是通过 ccaat/增强子结合蛋白 β (c/ebp)。这种基本的亮氨酸-拉链(bZIP)转录因子受寿命调节因子机械/哺乳动物靶蛋白雷帕霉素复合物1(mTORC1)控制,在能量平衡和脂肪组织分化中发挥重要作用。有证据表明,c/ebp 蛋白通过10-11易位(TET)甲基胞嘧啶双加氧酶及其适应蛋白的生长停滞和 DNA 损伤诱导蛋白45α (gadd45)及生长抑制剂1(ING1)调控其进入同源结合位点。我们讨论了新兴的因果关系之间的 c/ebp,能量代谢,和 DNA 去甲基化在生物体衰老。

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