Primate-restricted KRAB zinc finger proteins and target retrotransposons control gene expression in human neurons

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 coopted 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 (ESC). 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 interferonlike response. Thus, evolutionarily recent KZFPs and their TE targets partner up to influence human neuronal differentiation and physiology.One Sentence Summary: Young transposable elements and their protein controllers team up to regulate the differentiation and function of human neurons. Main Text:Some 4.5 million transposable element (TE)-derived sequences are disseminated across the human genome, many of which integrated within the last few tens of million years (1). TEs are typically enriched in transcription factor (TF) binding sites, and correspondingly influence gene expression in a broad range of biological events (2-5). However, TEeRS are silenced during the earliest phase of embryogenesis by KZFPs, which dock KAP1 (KRAB-associated protein 1, a.k.a. TRIM28) and associated heterochromatin inducers to TE loci (6-8). The rapid evolutionary selection of KZFP genes was initially interpreted as solely reflecting the host component of an arms race, but recent data suggest that KZFPs team up with TEs to build species-restricted layers of epigenetic regulation (8,9). The present work provides direct support for this model.We previously determined that a 35bp-long TE sequence encompassing the HERVK14C primer binding site (PBS)-encoding region (coined HERVK-R) confers KAP1-induced repression to a nearby PGK promoter in hESC (10). As part of a large-scale screen, we identified ZNF417 and ZNF587 as selectively enriched at loci containing this HERVK sequence (9). Depleting these two KZFPs from hESC restored expression of an HERVK-Rcontaining PGK-GFP lentivector (LV) (Fig. 1A), while producing them in murine ESCs silenced this vector, demonstrating the sequence-specific repressor potential of ZNF417 and ZNF587 and the likely absence of mouse orthologue ( fig. S1A). Phylogenetic analyses confirmed that ZNF417 emerged in the human ancestral genome ahead of the New World Monkey split 43 million years ago and that ZNF587 arose by duplication some 24 million years later ( fig. S1, B and C). ZNF417 and ZNF587 display 98% amino acid homology with some

Transposable elements as new players in neurodegenerative diseases

“…Epigenetic modifier drugs (DNMT and HDAC inhibitors) induce transcription from LTRs and lead to a high number of chimeric RNAs [177]. It was recently shown that primate‐specific KRAB zinc finger proteins and their target retrotransposons control gene expression in human neurons [178]. Activation of LINE‐1 elements was also shown in human neuronal progenitors following global DNA demethylation [12].…”

Developmental Dynamics of RNA Translation in the Human Brain

“…To identify ORFs whose start codons derive from transposable elements, we intersected our ORF start codons with a TE annotation kindly provided by the lab of Dr. Didier Trono. 60 First, we created a list of all start codons in different categories (protein-coding, lncRNA, uORF, sORF, pseudogene) by collapsing all ORFs that share a start position. We extended this start codon position to a 10 bp window and intersected this with a bed file of all TEs in the human genome using BedTools.…”

Transposable elements contribute to the spatiotemporal microRNA landscape in human brain development

“…S1) (Miller et al 2014; Li et al 2018). To enrich for different small RNA moieties, we separated sequencing reads into lengths of 18 - 25bp, 26 – 37bp and 38 – 50bp and intersected with Ensembl annotations, miRBase, the GtRNAdb database and our modified merged TE RepeatMasker data set (Kozomara and Griffiths-Jones 2014; Chan and Lowe 2016; Pontis et al 2019; Turelli et al 2020; Yates et al 2019; Playfoot et al 2021). As expected, the different read lengths enriched for annotated miRNAs, tRNAs and snoRNAs respectively (Fig.…”