Abstract
Krüppel‐associated box (KRAB)‐containing zinc finger proteins (KZFPs) are encoded in the hundreds by the genomes of higher vertebrates, and many act with the heterochromatin‐inducing KAP1 as repressors of transposable elements (TEs) during early embryogenesis. Yet, their widespread expression in adult tissues and enrichment at other genetic loci indicate additional roles. Here, we characterized the protein interactome of 101 of the ~350 human KZFPs. Consistent with their targeting of TEs, most KZFPs conserved up to placental mammals essentially recruit KAP1 and associated effectors. In contrast, a subset of more ancient KZFPs rather interacts with factors related to functions such as genome architecture or RNA processing. Nevertheless, KZFPs from coelacanth, our most distant KZFP‐encoding relative, bind the cognate KAP1. These results support a hypothetical model whereby KZFPs first emerged as TE‐controlling repressors, were continuously renewed by turnover of their hosts’ TE loads, and occasionally produced derivatives that escaped this evolutionary flushing by development and exaptation of novel functions.
Highlights
KZFP genes emerged in the last common ancestor of coelacanth (Latimeria chalumnae), lungfishes, and tetrapods some 413 million years ago (MYA) (Imbeault et al, 2017)
Owing to the large number of tested baits and the lack of antibodies allowing for an efficient purification of their endogenous versions, we relied on the overexpression of tagged proteins in 293T cells
In addition to the use of biological replicates, SAINT probabilistic scoring, batch-specific fold-change-over-control normalization, and subcellular localization-based filters allowed us to establish a high-confidence list of interactors. This was supported by our verification that a substantial subset of the interactions detected through our approach had been previously documented in different experimental settings
Summary
KZFP genes emerged in the last common ancestor of coelacanth (Latimeria chalumnae), lungfishes, and tetrapods some 413 million years ago (MYA) (Imbeault et al, 2017). Their products harbor an N-terminal KRAB (Kruppel-associated box) domain related to that of Meisetz (a.k.a. PRDM9), a protein that originated prior to the divergence of chordates and echinoderms, and a C-terminal array of zinc fingers (ZNF) with sequence-specific DNA-binding potential (Urrutia, 2003; Birtle & Ponting, 2006; Imbeault et al, 2017). More ancient family members do not bind recognizable TEs but are rather found at promoters or over gene bodies (Frietze et al, 2010a,b; Imbeault et al, 2017)
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