基因转录和 DNA 甲基化的改变是许多肝脏疾病的特征，包括脂肪肝和肝癌。然而，尚不清楚 DNA 甲基化变化是转录变化的原因还是结果。甚至有可能甲基化变化并不是转录变化所必需的。如果 DNA 甲基化只是肝脏转录变化的一个次要因素，或者是肝脏转录变化的结果，那么该领域的未来研究应该集中在其他系统上，例如组蛋白尾部修饰。为了探究 DNA 从头甲基化的重要性，我们培育了出生后肝脏中 Dnmt3a 和 Dnmt3b 纯合突变体的小鼠。这些小鼠具有正常大小的肝脏，能够存活且具有生育能力。男性（而非女性）表现出脂肪储备增加，但矛盾的是，控制饮食和高脂饮食（HFD）的葡萄糖耐量均有所改善。通过 RNA 测序和全基因组亚硫酸氢盐测序对成人肝细胞的转录组和甲基化组进行比较，发现突变体中 CpG 丰富区域甲基化的广泛丧失并不会导致稳态转录调控的丧失。同样，HFD 诱导的广泛转录变化不需要从头 DNA 甲基化。 Dnmt3a/3b 突变小鼠代谢表型的改善可能是通过葡萄糖和脂肪代谢基因子集的失调介导的，这些基因增加了肝脏的葡萄糖摄取和脂质输出。然而，还需要进一步的工作来证实这一点。© 2024 作者。 FASEB 期刊由 Wiley periodicals LLC 代表美国实验生物学学会联合会出版。

Alterations to gene transcription and DNA methylation are a feature of many liver diseases including fatty liver disease and liver cancer. However, it is unclear whether the DNA methylation changes are a cause or a consequence of the transcriptional changes. It is even possible that the methylation changes are not required for the transcriptional changes. If DNA methylation is just a minor player in, or a consequence of liver transcriptional change, then future studies in this area should focus on other systems such as histone tail modifications. To interrogate the importance of de novo DNA methylation, we generated mice that are homozygous mutants for both Dnmt3a and Dnmt3b in post-natal liver. These mice are viable and fertile with normal sized livers. Males, but not females, showed increased adipose depots, yet paradoxically, improved glucose tolerance on both control diet and high-fat diets (HFD). Comparison of the transcriptome and methylome with RNA sequencing and whole-genome bisulfite sequencing in adult hepatocytes revealed that widespread loss of methylation in CpG-rich regions in the mutant did not induce loss of homeostatic transcriptional regulation. Similarly, extensive transcriptional changes induced by HFD did not require de novo DNA methylation. The improved metabolic phenotype of the Dnmt3a/3b mutant mice may be mediated through the dysregulation of a subset of glucose and fat metabolism genes which increase both glucose uptake and lipid export by the liver. However, further work is needed to confirm this.© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.