Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20892, USA.
Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sci Adv. 2023 Feb 15;9(7):eadd2911. doi: 10.1126/sciadv.add2911.
Advanced human cognition is attributed to increased neocortex size and complexity, but the underlying evolutionary and regulatory mechanisms are largely unknown. Using human and macaque embryonic neocortical H3K27ac data coupled with a deep learning model of enhancers, we identified ~4000 enhancer gains in humans, which, per our model, can often be attributed to single-nucleotide essential mutations. Our analyses suggest that functional gains in embryonic brain development are associated with de novo enhancers whose putative target genes exhibit increased expression in progenitor cells and interneurons and partake in critical neural developmental processes. Essential mutations alter enhancer activity through altered binding of key transcription factors (TFs) of embryonic neocortex, including ISL1, POU3F2, PITX1/2, and several SOX TFs, and are associated with central nervous system disorders. Overall, our results suggest that essential mutations lead to gain of embryonic neocortex enhancers, which orchestrate expression of genes involved in critical developmental processes associated with human cognition.
高级人类认知归因于新大脑皮层大小和复杂性的增加，但潜在的进化和调节机制在很大程度上是未知的。使用人类和猕猴胚胎新大脑皮层 H3K27ac 数据以及增强子的深度学习模型，我们在人类中鉴定出约 4000 个增强子获得，根据我们的模型，这些增强子获得通常归因于单核苷酸必需突变。我们的分析表明，胚胎大脑发育中的功能获得与从头（de novo）增强子相关，其假定的靶基因在祖细胞和中间神经元中表达增加，并参与关键的神经发育过程。必需突变通过改变胚胎新大脑皮层关键转录因子（TFs）的结合来改变增强子活性，包括 ISL1、POU3F2、PITX1/2 和几个 SOX TFs，并与中枢神经系统疾病相关。总的来说，我们的结果表明，必需突变导致胚胎新大脑皮层增强子获得，这些增强子协调参与与人类认知相关的关键发育过程的基因表达。
