Swammerdam Institute for Life Sciences, Evolutionary Neurogenomics, University of Amsterdam, Amsterdam, The Netherlands.
Complex Trait Genetics, Amsterdam Neuroscience, Amsterdam, The Netherlands.
Genome Biol Evol. 2023 Nov 1;15(11). doi: 10.1093/gbe/evad184.
Krüppel-associated box (KRAB) zinc finger proteins (KZNFs) recognize and repress transposable elements (TEs); TEs are DNA elements that are capable of replicating themselves throughout our genomes with potentially harmful consequences. However, genes from this family of transcription factors have a much wider potential for genomic regulation. KZNFs have become integrated into gene-regulatory networks through the control of TEs that function as enhancers and gene promoters; some KZNFs also bind directly to gene promoters, suggesting an additional, more direct layer of KZNF co-option into gene-regulatory networks. Binding site analysis of ZNF519, ZNF441, and ZNF468 suggests the structural evolution of KZNFs to recognize TEs can result in coincidental binding to gene promoters independent of TE sequences. We show a higher rate of sequence turnover in gene promoter KZNF binding sites than neighboring regions, implying a selective pressure is being applied by the binding of a KZNF. Through CRISPR/Cas9 mediated genetic deletion of ZNF519, ZNF441, and ZNF468, we provide further evidence for genome-wide co-option of the KZNF-mediated gene-regulatory functions; KZNF knockout leads to changes in expression of KZNF-bound genes in neuronal lineages. Finally, we show that the opposite can be established upon KZNF overexpression, further strengthening the support for the role of KZNFs as bona-fide gene regulators. With no eminent role for ZNF519 in controlling its TE target, our study may provide a snapshot into the early stages of the completed co-option of a KZNF, showing the lasting, multilayered impact that retrovirus invasions and host response mechanisms can have upon the evolution of our genomes.
Krüppel 相关盒子 (KRAB) 锌指蛋白 (KZNFs) 识别并抑制转座元件 (TEs)；TEs 是能够在我们的基因组中自我复制的 DNA 元件，可能会产生有害的后果。然而，这个转录因子家族的基因在基因组调节方面具有更广泛的潜在作用。KZNFs 通过控制作为增强子和基因启动子的 TEs 而整合到基因调控网络中；一些 KZNFs 也直接结合到基因启动子上，这表明 KZNF 被更多直接地纳入基因调控网络。ZNF519、ZNF441 和 ZNF468 的结合位点分析表明，KZNF 识别 TEs 的结构进化可以导致与 TE 序列无关的基因启动子的偶然结合。我们发现基因启动子 KZNF 结合位点的序列周转率高于邻近区域，这意味着 KZNF 的结合施加了选择压力。通过 CRISPR/Cas9 介导的 ZNF519、ZNF441 和 ZNF468 基因缺失，我们进一步提供了 KZNF 介导的基因调控功能在全基因组范围内被广泛选择的证据；KZNF 敲除导致神经谱系中 KZNF 结合基因的表达变化。最后，我们表明，在 KZNF 过表达时可以建立相反的情况，进一步加强了 KZNFs 作为真正基因调节剂的作用。由于 ZNF519 在控制其 TE 靶标方面没有突出的作用，我们的研究可能提供了 KZNF 完全被选择的早期阶段的一个快照，展示了逆转录病毒入侵和宿主反应机制对我们基因组进化的持久、多层次的影响。
