Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons
Priscilla Turelli, Christopher J. Playfoot, Dephine Grun, Charlène Raclot, Julien Pontis, Alexandre Coudray, Christian W. Thorball, Julien Duc, Eugenia V. Pankevich, Bart Deplancke, Volker Busskamp, Didier Trono
Abstract
In the first days of embryogenesis, transposable element-embedded regulatory sequences (TEeRS) are silenced by Kruppel-associated box (KRAB) zinc finger proteins (KZFPs). Many TEeRS are subsequently co-opted in transcription networks, but how KZFPs influence this process is largely unknown. We identify ZNF417 and ZNF587 as primate-specific KZFPs repressing HERVK (human endogenous retrovirus K) and SVA (SINE-VNTR-Alu) integrants in human embryonic stem cells (ESCs). Expressed in specific regions of the human developing and adult brain, ZNF417/587 keep controlling TEeRS in ESC-derived neurons and brain organoids, secondarily influencing the differentiation and neurotransmission profile of neurons and preventing the induction of neurotoxic retroviral proteins and an interferon-like response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.