Department of Cellular and Molecular Medicine, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Center for Epigenomics, University of California, San Diego School of Medicine, La Jolla, CA, USA.
Nature. 2023 Dec;624(7991):390-402. doi: 10.1038/s41586-023-06819-6. Epub 2023 Dec 13.
Divergence of cis-regulatory elements drives species-specific traits, but how this manifests in the evolution of the neocortex at the molecular and cellular level remains unclear. Here we investigated the gene regulatory programs in the primary motor cortex of human, macaque, marmoset and mouse using single-cell multiomics assays, generating gene expression, chromatin accessibility, DNA methylome and chromosomal conformation profiles from a total of over 200,000 cells. From these data, we show evidence that divergence of transcription factor expression corresponds to species-specific epigenome landscapes. We find that conserved and divergent gene regulatory features are reflected in the evolution of the three-dimensional genome. Transposable elements contribute to nearly 80% of the human-specific candidate cis-regulatory elements in cortical cells. Through machine learning, we develop sequence-based predictors of candidate cis-regulatory elements in different species and demonstrate that the genomic regulatory syntax is highly preserved from rodents to primates. Finally, we show that epigenetic conservation combined with sequence similarity helps to uncover functional cis-regulatory elements and enhances our ability to interpret genetic variants contributing to neurological disease and traits.
顺式调控元件的差异导致了物种特有的特征，但这在分子和细胞水平上是如何体现在新皮层的进化中的仍然不清楚。在这里，我们使用单细胞多组学分析方法研究了人类、猕猴、绒猴和小鼠的初级运动皮层中的基因调控程序，总共从超过 200,000 个细胞中生成了基因表达、染色质可及性、DNA 甲基化组和染色体构象图谱。从这些数据中，我们证明了转录因子表达的差异与物种特异性的表观基因组景观相对应。我们发现保守和差异的基因调控特征反映在三维基因组的进化中。转座元件几乎占皮质细胞中人类特异性候选顺式调控元件的 80%。通过机器学习，我们为不同物种的候选顺式调控元件开发了基于序列的预测器，并证明了从啮齿动物到灵长类动物的基因组调控语法高度保守。最后，我们表明，表观遗传保守性结合序列相似性有助于揭示功能顺式调控元件，并提高我们解释导致神经疾病和特征的遗传变异的能力。
