Regulation of endogenous retroelements by KRAB-ZFP proteins

Regulation of endogenous retroelements by KRAB-ZFP proteins Krüppel-associated box domain (KRAB) zinc finger proteins (KRAB-ZFPs) contain a transcriptionally repressive N-terminal domain, the KRAB domain, and a C-terminal domain, the ZFP domain, that contains 2-40 zinc fingers and binds specific sequences of DNA (reviewed in Ecco et al. 2017, Yang et al. 2017). The human genome contains about 352 (Lukic et al. 2014), 378 (de Tribolet-Hardy et al. 2023), or 423 (Huntley et al. 2006) KRAB-ZFP genes, making them the largest family of transcription regulators.
About two thirds or more of KRAB-ZFPs bind transposable elements (Schmitges et al. 2016, Imbeault et al. 2017, de Tribolet-Hardy et al. 2023) and KRAB-ZFPs appear to coevolve with retroelements such that a KRAB-ZFP binds and transcriptionally silences a specific set of retroelements (reviewed in Ecco et al. 2017). The number of KRAB-ZFP genes correlates with the number of retroelements in mammalian genomes and younger retroelements bind fewer KRAB-ZFPs, suggesting an "arms race" in which the evolution of new KRAB-ZFPs is driven by and lags the appearance of new transposable elements (Thomas and Schneider 2011, Jacobs et al. 2014, Imbeault et al. 2017, reviewed in Ecco et al. 2017, Yang et al. 2017).
The repressive action of KRAB-ZFPs is mediated by the scaffold protein TRIM28 (also called KAP1), the RBCC domain of which binds the N-terminal KRAB domains of KRAB-ZFPs (Friedman et al. 1996). TRIM28 autoSUMOylates and recruits effectors, such as the histone H3 lysine-9 trimethyltransferase SETDB1 (also called ESET) (Schultz et al. 2002) and the NuRD repressor complex (Schultz et al. 2001).
The HUSH complex (MPHOSPH8:TASOR:PPHLN1) plays a nonredundant role with TRIM28 in silencing some young LINE1 retroelements, which are only weakly repressed by TRIM28 or HUSH alone (Robbez-Masson et al. 2018).