Abstract
KRAB-containing poly-zinc finger proteins (KZFPs) constitute the largest family of transcription factors encoded by mammalian genomes, and growing evidence indicates that they fulfill functions critical to both embryonic development and maintenance of adult homeostasis. KZFP genes underwent broad and independent waves of expansion in many higher vertebrates lineages, yet comprehensive studies of members harbored by a given species are scarce. Here we present a thorough analysis of KZFP genes and related units in the murine genome. We first identified about twice as many elements than previously annotated as either KZFP genes or pseudogenes, notably by assigning to this family an entity formerly considered as a large group of Satellite repeats. We then could delineate an organization in clusters distributed throughout the genome, with signs of recombination, translocation, duplication and seeding of new sites by retrotransposition of KZFP genes and related genetic units (KZFP/rGUs). Moreover, we harvested evidence indicating that closely related paralogs had evolved through both drifting and shifting of sequences encoding for zinc finger arrays. Finally, we could demonstrate that the KAP1-SETDB1 repressor complex tames the expression of KZFP/rGUs within clusters, yet that the primary targets of this regulation are not the KZFP/rGUs themselves but enhancers contained in neighboring endogenous retroelements and that, underneath, KZFPs conserve highly individualized patterns of expression.
Highlights
Dynamic changes in gene super-families are potent drivers of evolution and diversity across species [1, 2]
The repository of murine repetitive elements lists as a member of the Satellite family a simple repeat named ‘MMSAT4’, the consensus sequence of which was derived from arrays of triplets of C2H2 zinc fingers (ZNFs) located on chromosome 4 (Fig 1A, http://www.girinst.org/repbase/ [32])
More evolutionary conserved clusters contain young KRAB-containing zinc finger proteins (KZFPs)/rGUs, indicating that they too have been subjected to recent expansion
Summary
Dynamic changes in gene super-families are potent drivers of evolution and diversity across species [1, 2]. KZFP genes were subsequently amplified as the apparent result of adaptive expansion and contraction events [5,6,7], while being subjected to intense positive selection, so as to constitute today a large repertoire of species-specific TFs [8,9,10,11,12]. This pattern of evolution likely reflects the involvement of KZFPs in the early embryonic repression of endogenous retroelements (EREs), many of which are themselves lineage- or species-restricted [13,14,15].
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