Transposable elements drive the evolution of metazoan zinc finger genes

Abstract

Cys2-His2 Zinc finger genes (ZNFs) form the largest family of transcription factors in metazoans. ZNF evolution is highly dynamic and characterized by the rapid expansion and contraction of numerous subfamilies across the animal phylogeny. The forces and mechanisms underlying rapid ZNF evolution remain poorly understood, but there is growing evidence that the targeting and repression of lineage-specific transposable elements (TEs) plays a major role in the diversification of the Kruppel-associated box ZNF (KZNF) subfamily, which predominates in tetrapod genomes. At present, it is unknown whether this function and co-evolutionary relationship is unique to KZNFs, or a broader feature of metazoan ZNFs. Here, we present evidence that genomic conflict with TEs has been a central driver in the diversification of ZNFs in animals. Sampling from more than 4000 animal genome assemblies, we show that the copy number of retroelements correlates with that of ZNFs across at least 750 million years of metazoan evolution, both within and between major taxonomic groups. Using computational predictions, we show that ZNFs preferentially bind TEs in a diverse set of representative animal species. We further investigate one of the most expansive ZNF subfamilies found in cyprinid fish, which are characterized by a conserved domain we dubbed theFishN-terminalZinc-finger associated (FiNZ) domain. FiNZ-ZNFs have dramatically expanded in several fish species, including the zebrafish in which we predict ~700 FiNZ-ZNF genes. Almost all are located on the long arm of chromosome 4, and recent duplicates are evolving adaptively under positive selection. Like mammalian KZNFs, the bulk of zebrafish FiNZ-ZNFs are expressed in waves at the onset of zygotic genome activation. Blocking FiNZ-ZNF translation using morpholinos during early zebrafish embryogenesis results in a global de-repression of young, transcriptionally active TEs, likely driven by the failure to establish heterochromatin over these elements. Together, these data suggest that ZNF diversification has been intimately connected to TE expansion throughout animal evolution and that families of ZNFs have been deployed independently in fish and mammals to repress TEs during early embryogenesis.

Universal signatures of transposable element compartmentalization across eukaryotic genomes

“…We observe similar patterns for zinc finger (ZF) genes in metazoans, despite their poor annotation in most genomes (Figure 1E). ZFs are the most abundant transcription factors in metazoans and evolve rapidly under strong selective pressure due important for host defense against transposable elements (Figure 1E) 51 . In plants such as Arabadopsis thaliana , we also find vital gene families for plant defense such as RING protein genes, leucine-rich repeat genes, and defensins, consistent with previous reports (Figure 1F) 5,17,52,53 .…”

A maternal-to-zygotic-transition gene block on the zebrafish sex chromosome

“…B. Reciprocally, early embryos at the beginning of the maternal-to-zygotic transition do not express maternal 5S rRNA or maternal spliceosome (U1, U6) genes in Region-2, but do express Region-2 znf genes and the nearby mir430 genes. Znf proteins may help to stabilize the mobility of transposable elements (White et al 2017; Hadzhiev et al 2019; Wells et al 2023) and the mir430 mature products promote clearance of maternal messenger RNAs (Giraldez et al 2005; Takacs and Giraldez 2016; Giraldez et al 2006; Lund et al 2009). Abbreviations: R1, R2, R3, and R4 represent Regions-1 to −4.…”

“…6B). The role of at least some proteins encoded by these activated Region-2 znf genes appears to be to repress the expression of retroelements during zygotic genome activation (ZGA) (White et al 2017; Hadzhiev et al 2019; Wells et al 2023), and without that suppression, early development goes awry. Autosomal copies of translation machinery genes, including snRNA genes, ribosomal RNA genes, and we predict tRNA genes, become active (Locati et al 2017a; Locati et al 2018; Locati et al 2017b; Pagano et al 2020a; Pagano et al 2020b), replace the maternal translation machinery, and translate zygotic mRNAs as the embryo transitions to the use of its own genome.…”

Mini-heterochromatin domains constrain thecis-regulatory impact of SVA transposons in human brain development and disease

“…To protect genomic integrity against TE insertions, organisms have evolved cellular defense mechanisms 45,46 . KZFP genes have amplified and diversified in mammalian species in response to transposon colonization [47][48][49][50][51][52] ; recent profiling efforts have identified several KZFPs that bind to SVAs, including ZNF91 and ZNF611 29,50,53 . We noted that ZNF91 is highly expressed in human fetal forebrain tissue and XDP-and Ctrl-NPC cultures, as monitored by bulk and snRNA-seq (Figure 2E-G) 54 .…”