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 speciesspecific 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.

The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution

“…Considering the large number of KRAB-ZFPs and TEs in mammalian genomes, it is likely that hundreds, if not thousands, of genes are indirectly regulated by KRAB-ZFPs through TEs proximal effects. These findings have led to speculation that the expansion and selection of KRAB-ZFP binding to TEs was not driven solely by the need to directly suppress TE expression, but was instead an engine driving the domestication of TE derived regulatory sequences (Box 2) [71]. According to this model, continuous innovation and spread of TEs along with their KRAB-ZFPs binders rewires gene expression networks in each species, potentially impacting many aspects of organismal development and physiology.…”

“…These non-TE binding KRAB-ZFPs are more ancient (evolutionarily speaking) and thus it is possible that some or even most were originally TE binders, but over time their target TE sequences eroded due to genetic drift. Regardless of how such non-TE binding KRAB-ZFPs evolved, there is a growing body of literature into the gene regulatory functions of these proteins, which have been recently extensively reviewed [71]. We will focus attention on three KRAB-ZFPs that are not found in clusters and are implicated in essential vertebrate and mammalian regulatory innovations: ZFP57, the master regulator of genomic imprinting, ZFP568, which represses a placental isoform of the master fetal growth hormone insulin like growth factor 2 (IGF2), and PRDM9, the ancestor of all KRAB-ZFPs and the master regulator of recombination site selection during meiosis.…”

What Doesn't Kill You Makes You Stronger: Transposons as Dual Players in Chromatin Regulation and Genomic Variation

“…[26]). Distinct KRAB‐ZFPs selectively recognize ERVs and LINE1 and recruit KAP1 to silence them via formation of heterochromatin . The HUSH complex and MORC2 have also been shown to target evolutionarily young euchromatic LINE1 elements for silencing by deposition of H3K9me3 .…”

CRISPR-based reagents to study the influence of the epigenome on gene expression

“…2a). These reagents can bypass the epigenetic constraints of gene expression within a cell and have been used for a variety of genomewide screens to efficiently silence either single or multiple genes or silence the influence of regulatory domains in the native genomic context 49, 50, 51, 52, 53, 54, 55, 56, 57, 58.…”