Glinsky Gennadi, Barakat Tahsin Stefan
Institute of Engineering in Medicine, University of California San Diego, 9500 Gilman Dr. MC 0435, La Jolla, CA 92093-0435, USA.
Department of Clinical Genetics, Erasmus MC, University Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands.
Stem Cell Res. 2019 May;37:101456. doi: 10.1016/j.scr.2019.101456. Epub 2019 May 3.
High-throughput functional assays of enhancer activity have recently enabled the genome-scale definition of molecular, structural, and biochemical features of these genomic regulatory regions. To infer the evolutionary origin of DNA sequences operating as functional enhancers in human embryonic stem cells (hESC), we examined the patterns of evolutionary conservation and divergence in the genome-wide functional enhancers' landscape of hESC. We show that a prominent majority (up to 94%) of DNA sequences identified in hESC as functional enhancers are conserved in humans and our closest evolutionary relatives, Chimpanzee and Bonobo. More than 91% of functional enhancers that are highly conserved in both Chimpanzee and Bonobo, are conserved among other Great Apes and >75% are conserved in the Rhesus genome. In striking contrast, <5% of DNA sequences operating in hESC as functional enhancers are conserved in rodents. Conserved in primates enhancers' sequences are complemented by 1619 sequences of enhancers that are specific to humans. Enhancers that harbor human-specific sequences appear enriched among the invariant enhancer module maintaining activity in different pluripotent states and these regions are associated with pluripotency- and embryonic-lineage-related genes. However, functional enhancers make up only a minority of all conserved in primates or human-specific transcription factor binding sites. Our analyses revealed that sequences that are conserved during ~8 million years of primate evolution dominate the genomic landscape of functional enhancers in both primed and naïve hESC. Collectively, these observations revealed thousands of evolutionarily conserved sequences that function as a core regulatory network in human embryonic stem cells which has recently undergone further extension after divergence of modern humans from our closest relatives, Chimpanzee and Bonobo.
最近，高通量增强子活性功能分析使得对这些基因组调控区域的分子、结构和生化特征进行全基因组规模的定义成为可能。为了推断在人类胚胎干细胞（hESC）中作为功能性增强子的DNA序列的进化起源，我们研究了hESC全基因组功能增强子景观中的进化保守和分歧模式。我们发现，在hESC中被鉴定为功能性增强子的DNA序列中，绝大多数（高达94%）在人类以及我们最亲近的进化亲属黑猩猩和倭黑猩猩中是保守的。在黑猩猩和倭黑猩猩中都高度保守的功能性增强子中，超过91%在其他大猿中是保守的，超过75%在恒河猴基因组中是保守的。与之形成鲜明对比的是，在hESC中作为功能性增强子起作用的DNA序列中，只有不到5%在啮齿动物中是保守的。灵长类动物中保守的增强子序列由1619个特定于人类的增强子序列补充。含有人类特异性序列的增强子在维持不同多能状态活性的不变增强子模块中似乎富集，并且这些区域与多能性和胚胎谱系相关基因有关。然而，功能性增强子仅占所有在灵长类动物中保守的或人类特异性转录因子结合位点的少数。我们的分析表明，在约800万年的灵长类动物进化过程中保守的序列主导了原始态和幼稚态hESC中功能性增强子的基因组景观。总体而言，这些观察结果揭示了数千个进化保守序列，它们在人类胚胎干细胞中作为核心调控网络发挥作用，在现代人类与我们最亲近的亲属黑猩猩和倭黑猩猩分化后，该网络最近又经历了进一步扩展。
