基因调控变化被认为是物种之间表现差异的潜在原因。对于裸鼠等地下啮齿动物，拟议的表型适应包括耐低氧、代谢变化和抗癌能力。然而，如何与这些表型特征相关的调控变化尚不清楚，并且不知道这些变化是裸鼠特有的，还是在其他哺乳动物中也存在。本文通过基因组范围的表观基因组分析，研究了两种非洲鼹鼠和两个啮齿类外群动物的心脏和肝脏的调控进化。首先，我们采用了一种系统发育建模方法，定量比较了正交调控元件的表观信号，并鉴定出裸鼠中具有差异表观基因组活性的数千个启动子和增强子区域。这些元素与裸鼠代谢和功能适应的已知途径相关，并提示可能支持裸鼠创新的候选遗传位点。其次，我们评估了研究系统发育树中的祖先和物种特异的调控变化，并报告了几条在鼹鼠进化过程中经历逐步重塑的候选途径，如胰岛素和低氧应答途径。第三，我们报告了非正交调控元件与线虫特异的重复元件重叠，并似乎通过重构裸鼠中HNF4和RAR/RXR转录因子结合位点来调节代谢途径。这些比较分析揭示了鼹鼠调控演化如何揭示先前报道的表型适应。此外，我们提出的系统发育建模框架改进了当前在跨物种表观基因组比较中已知的限制，并在比较功能基因组学领域具有广泛意义。由 Cold Spring Harbor 实验室出版。

Changes in gene regulation are thought to underlie most phenotypic differences between species. For subterranean rodents such as the naked mole-rat, proposed phenotypic adaptations include hypoxia tolerance, metabolic changes and cancer resistance. However, it is largely unknown what regulatory changes may associate with these phenotypic traits, and whether these are unique to the naked mole-rat, the mole-rat clade or also present in other mammals. Here, we investigate regulatory evolution in heart and liver from two African mole-rat species and two rodent outgroups using genome-wide epigenomic profiling. First, we adapted and applied a phylogenetic modeling approach to quantitatively compare epigenomic signals at orthologous regulatory elements, and identified thousands of promoter and enhancer regions with differential epigenomic activity in mole-rats. These elements associate with known mole-rat adaptation in metabolic and functional pathways, and suggest candidate genetic loci that may underlie mole-rat innovations. Second, we evaluated ancestral and species-specific regulatory changes in the study phylogeny, and report several candidate pathways experiencing stepwise remodeling during the evolution of mole-rats, such as the insulin and hypoxia response pathways. Third, we report nonorthologous regulatory elements overlap with lineage-specific repetitive elements and appear to modify metabolic pathways by rewiring of HNF4 and RAR/RXR transcription factor binding sites in mole-rats. These comparative analyses reveal how mole-rat regulatory evolution informs previously reported phenotypic adaptations. Moreover, the phylogenetic modeling framework we propose here improves upon the state-of-the-art by addressing known limitations of inter-species comparisons of epigenomic profiles, and has broad implications in the field of comparative functional genomics.Published by Cold Spring Harbor Laboratory Press.