Department of Biochemistry and Molecular Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Development. 2022 Oct 1;149(19). doi: 10.1242/dev.200413. Epub 2022 Oct 4.
The hippocampus is associated with essential brain functions, such as learning and memory. Human hippocampal volume is significantly greater than expected compared with that of non-human apes, suggesting a recent expansion. Intermediate progenitors, which are able to undergo multiple rounds of proliferative division before a final neurogenic division, may have played a role in evolutionary hippocampal expansion. To investigate the evolution of gene regulatory networks underpinning hippocampal neurogenesis in apes, we leveraged the differentiation of human and chimpanzee induced pluripotent stem cells into TBR2 (or EOMES)-positive hippocampal intermediate progenitor cells (hpIPCs). We found that the gene networks active in hpIPCs are significantly different between humans and chimpanzees, with ∼2500 genes being differentially expressed. We demonstrate that species-specific transposon-derived enhancers contribute to these transcriptomic differences. Young transposons, predominantly endogenous retroviruses and SINE-Vntr-Alus (SVAs), were co-opted as enhancers in a species-specific manner. Human-specific SVAs provided substrates for thousands of novel TBR2-binding sites, and CRISPR-mediated repression of these SVAs attenuated the expression of ∼25% of the genes that are upregulated in human intermediate progenitors relative to the same cell population in the chimpanzee.
海马体与学习和记忆等基本大脑功能有关。与非人类猿类相比，人类的海马体体积明显更大，这表明其近期有所扩张。能够进行多次增殖分裂，然后进行最终的神经发生分裂的中间祖细胞，可能在进化中海马扩张中发挥了作用。为了研究支持猿类海马神经发生的基因调控网络的进化，我们利用人类和黑猩猩诱导多能干细胞分化为 TBR2（或 EOMES）阳性海马中间祖细胞（hpIPCs）。我们发现，hpIPCs 中的基因网络在人类和黑猩猩之间存在显著差异，约有 2500 个基因表达存在差异。我们证明，物种特异性转座子衍生增强子导致了这些转录组差异。年轻的转座子，主要是内源性逆转录病毒和 SINE-Vntr-Alus（SVAs），以物种特异性的方式被募集为增强子。人类特异性 SVAs 为数千个新的 TBR2 结合位点提供了底物，CRISPR 介导的这些 SVA 的抑制减弱了相对于黑猩猩中相同细胞群体，在人类中间祖细胞中上调的约 25%基因的表达。
