The interactome of KRAB zinc finger proteins reveals the evolutionary history of their functional diversification. (12th August 2019)

• Record Type: Journal Article
• Authors: Helleboid, Pierre‐Yves; Heusel, Moritz; Duc, Julien; Piot, Cécile; Thorball, Christian W; Coluccio, Andrea; Pontis, Julien; Imbeault, Michaël; Turelli, Priscilla; Aebersold, Ruedi; Trono, Didier
• Is Part Of: EMBO journal. Volume 38:Number 18(2019)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-08-12
• Subjects: coelacanth -- evolution -- KAP1 -- KRAB zinc finger proteins -- mass spectrometry; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.2018101220
• Languages: English
• ISSNs: 0261-4189

Abstract

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. Synopsis: In this resource, elucidation of the interactome of 101 Krüppel‐associated box (KRAB)‐containing zinc finger proteins (KZFPs) offers insights into the evolution of this largest subfamily of human transcription factors and uncovers unexpected functions of its most ancient members. Evolutionarily young KZFPs interact with the co‐repressor KAP1 in order to repress transposable elements. Evolutionarily old KZFPs are weak KAP1 binders. More ancient KZFPs bind specific interactors, which include factors involved in chromatin organization and RNA metabolism. An examination of coelacanth KZFPs indicates that these proteins likely first emerged as bona fide repressors of transposable elements. Abstract : Comprehensive interaction mapping of the KRAB domain zinc finger transcription factor family shows conservation of their function in KAP1 binding and identifies novel binding partners of the most ancient members.