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ZNF675 evolutionary history and its novel role in neuronal regulatory networks
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ZNF675 is a primate-specific KRAB-ZNF protein that arose in the last common ancestor of New World Monkeys and Old World Monkeys. It represses THE1 and MST families of retrotransposons and binds to gene promoters like MCPH1 and SESN3. Copy-number variation of ZNF675 is associated with neurological disorders, including microcephaly and intellectual disability. Unravelling the evolutionary history and the regulatory effect of ZNF675 will clarify its role in primates’ evolution.
The analysis of ZNF675 sequence revealed a significant difference in zinc-finger domains between the marmoset and the human ZNF675. In a reporter assay, the marmoset ZNF675 did not bind to MSTA elements. However, the human ZNF675 had a strong repressive effect on them. This indicates structural changes in ZNF675 emerged to silence THE1 and MST retrotransposons, after New World Monkeys split from our last common ancestor. As a collateral effect, ZNF675 created a new regulatory network, by binding to gene promoters, 25% of which are involved in development and neuronal processes. At the same time, some ZNF675 binding sites in gene promoters also underwent changes, as found in the MCPH1 and SESN3 promoters. These changes affect the ZNF675 binding capacity and led to the evasion or stabilization of its regulatory function. This highlights the dynamics of genome evolution in primates.
To further investigate these findings, the CRISPR/Cas9 system was used for targeted deletion of ZNF675 and ZNF681, or for modifying promoter region sequences using homology-directed repair.
The evolutionary arms race between ZNF675 and THE1 and MST elements led to the creation of a novel ZNF675, with the ability to silence them. As a collateral consequence, ZNF675 binds to gene promoters, regulating their expression. This new regulation network might have had a strong impact on the evolution of the human brain.
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Palavras-chave
ZNF675 KRAB-ZNF protein retrotransposons gene regulation evolution brain