KRAB zinc finger proteins

Abstract

Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs) are the largest family of transcriptional regulators in higher vertebrates. Characterized by an N-terminal KRAB domain and a C-terminal array of DNA-binding zinc fingers, they participate, together with their co-factor KAP1 (also known as TRIM28), in repression of sequences derived from transposable elements (TEs). Until recently, KRAB-ZFP/KAP1-mediated repression of TEs was thought to lead to irreversible silencing, and the evolutionary selection of KRAB-ZFPs was considered to be just the host component of an arms race against TEs. However, recent advances indicate that KRAB-ZFPs and their TE targets also partner up to establish species-specific regulatory networks. Here, we provide an overview of the KRAB-ZFP gene family, highlighting how its evolutionary history is linked to that of TEs, and how KRAB-ZFPs influence multiple aspects of development and physiology.

Keywords: Co-option; Endovirome; Gene regulation; KRAB-ZFP; Speciation; Transposable element.

Figure 1. Classification of transposable elements.

The different classes of transposable elements and examples of their structures are depicted. LTR, long terminal repeat; Gag, group-specific antigen; Pol, polymerase; Env, envelope protein; UTR, untranslated region; ORF, open reading frame; (A)n, poly(A) tail; A and B, component sequences of the RNA polymerase III promoter; AR, the adenosine-rich segment separating the 7SL monomers; VNTR, variable number target repeats; ITR, inverted terminal repeat.

Figure 2. How transposable elements can impact on host genomes.

Figure 3. Domain structure of KZFPs.

All KZFPs contain a KRAB domain and an array of zinc fingers. Those are responsible for interacting with the DNA, and in each three amino acids (at positions 6, 3, and -1) are engaged in mediating contacts with DNA. KRAB, Krüppel-associated box; ZF, zinc finger; SCAN, SREZBP, CTfin51, AW-1, and Number 18 cDNA; DUF3669, domain of unknown function 3669.

Figure 4. The KRAB/KAP1 repressive complex.

KZFPs bind to DNA via their zinc fingers and recruit KAP1 via their KRAB domain. KAP1 then recruits components of a repressor complex, which leads to heterochromatin formation and transcriptional silencing. H3ac, acetylated histone H3; H3K9me3, histone H3 trimethylated at Lys9; NURD, nucleosome remodeling deacetylase complex; HDAC, histone deacetylase; KAP1, Krüppel-associated box (KRAB)-associated protein 1; KZFP, KRAB-zinc finger protein; SETDB1, SET domain bifurcated 1; HP1, heterochromatin protein 1; DNMT, DNA methyltransferase.

Figure 5. The dual evolutionary drive of KZFPs: arms race and TE domestication.

(A) KZFPs gene expansion over time. Duplication events and accumulation of mutations are depicted. (B) An evolutionary arms race between KZFPs and TEs. When a novel TE enters the host, it starts to be expressed and to transpose, albeit partly controlled by a first, small RNA-based, line of defense (1). Over time, KZFPs genes duplicate and paralogs emerge that can bind these TEs (2). In parallel, transposons accumulate mutations and escape repression (3 and 5), yet new KZFPs appear that can suppress the expression of these escapees (4 and 6). Eventually some of these TEs accumulate mutations and are rendered inactive (7) (C) From deleterious mutations to co-option. Left, a hypothetical gene would initially have a certain phenotypic impact (phenotypic impact 1). Middle, transposon insertions near genes can lead to transcriptional effects with phenotypic consequences (causing a phenotypic impact 2). Right, some of these could be beneficial for the host, notably if modulated by KZFP-mediated control, which can incur a variety of transcriptional and phenotypic effects. The TE/KZFP pair then can become fixed in evolution, completing the co-option process. KZFPs, KRAB-zinc finger proteins; TEs, transposable elements; TFs, transcription factors