Transposable elements (TEs) account for more than 50% of the human genome and many have been co-opted throughout evolution to provide regulatory functions for gene expression networks. Several lines of evidence suggest that these networks are fine-tuned by the largest family of TE controllers, the KRAB-containing zinc finger proteins (KZFPs). One tissue permissive for TE transcriptional activation (termed “transposcription”) is the adult human brain, however comprehensive studies on the extent of this process and its potential contribution to human brain development are lacking. To elucidate the spatiotemporal transposcriptome of the developing human brain, we have analyzed two independent RNA-seq data sets encompassing 16 brain regions from eight weeks postconception into adulthood. We reveal a distinct KZFP:TE transcriptional profile defining the late prenatal to early postnatal transition, and the spatiotemporal and cell type–specific activation of TE-derived alternative promoters driving the expression of neurogenesis-associated genes. Long-read sequencing confirmed these TE-driven isoforms as significant contributors to neurogenic transcripts. We also show experimentally that a co-opted antisense L2 element drives temporal protein relocalization away from the endoplasmic reticulum, suggestive of novel TE dependent protein function in primate evolution. This work highlights the widespread dynamic nature of the spatiotemporal KZFP:TE transcriptome and its importance throughout TE mediated genome innovation and neurotypical human brain development. To facilitate interactive exploration of these spatiotemporal gene and TE expression dynamics, we provide the “Brain TExplorer” web application freely accessible for the community.

中文翻译：

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转座元件及其 KZFP 控制器是人类大脑发育中转录创新的驱动力


转座元件 (TE) 占人类基因组的 50% 以上，并且许多转座元件在整个进化过程中被增选，为基因表达网络提供调节功能。多项证据表明，这些网络是由最大的 TE 控制器家族（含 KRAB 的锌指蛋白 (KZFP)）进行微调的。成人大脑是一种允许 TE 转录激活（称为“转座”）的组织，但目前还缺乏对该过程的程度及其对人类大脑发育的潜在贡献的全面研究。为了阐明发育中的人类大脑的时空转录组，我们分析了两个独立的 RNA-seq 数据集，涵盖从受孕后 8 周到成年期的 16 个大脑区域。我们揭示了独特的 KZFP:TE 转录谱，定义了产前晚期到产后早期的转变，以及驱动神经发生相关基因表达的 TE 衍生替代启动子的时空和细胞类型特异性激活。长读长测序证实这些 TE 驱动的亚型是神经源性转录本的重要贡献者。我们还通过实验证明，增选反义 L2 元件可驱动时间蛋白重新定位，使其远离内质网，这表明灵长类动物进化中存在新的 TE 依赖性蛋白功能。这项工作强调了时空 KZFP:TE 转录组的广泛动态性质及其在 TE 介导的基因组创新和神经典型人脑发育中的重要性。为了促进对这些时空基因和 TE 表达动态的交互式探索，我们提供了可供社区免费访问的“Brain TExplorer”网络应用程序。