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Abstract
Highly coordinated transcription networks orchestrate the self-renewal of pluripotent stem cell and the earliest steps of mammalian development. KRAB-containing zinc finger proteins represent the largest group of transcription factors encoded by the genomes of higher vertebrates including mice and humans. Together with their putatively universal cofactor KAP1, they have been implicated in events as diverse as the silencing of endogenous retroelements, the maintenance of imprinting and the pluripotent self-renewal of embryonic stem cells, although the genomic targets and specific functions of individual members of this gene family remain largely undefined. Here, we first generated a list of Ensembl-annotated KRAB-containing genes encoding the mouse and human genomes. We then defined the transcription levels of these genes in murine early embryonic cells. We found that the majority of KRAB-ZFP genes are expressed in mouse pluripotent stem cells and other early progenitors. However, we also identified distinctively cell- or stage-specific patterns of expression, some of which are pluripotency-restricted. Finally, we determined that individual KRAB-ZFP genes exhibit highly distinctive modes of expression, even when grouped in genomic clusters, and that these cannot be correlated with the presence of prototypic repressive or activating chromatin marks. These results pave the way to delineating the role of specific KRAB-ZFPs in early embryogenesis.
Highlights
About two thirds of the some 1500 transcription factors (TFs) encoded by mammalian genomes contain C2H2 zinc-fingers (ZF) allowing for sequence-specific binding to polynucleotidic sequences [1,2]
We first updated the list of Ensembl mouse genes encoding for KRAB-Zinc-finger proteins (ZFPs) or KRAB-O proteins by interrogating four protein databases for accession IDs corresponding to the conserved structure of the KRAB domain (PF01352, IPR001909, SM00349 and PS50805, respectively), and using these as filters on the Martview tool of the BioMart project to obtain a list of unique Ensembl Gene IDs
Comparing our list with that previously obtained by Emerson and Thomas based on a 2009 genome annotation [1] revealed 95 previously not recorded protein-coding Ensembl KRAB-ZFP genes, while only one identified in this other study was missed by our approach (Figure 1b, Table S2)
Summary
About two thirds of the some 1500 transcription factors (TFs) encoded by mammalian genomes contain C2H2 zinc-fingers (ZF) allowing for sequence-specific binding to polynucleotidic sequences [1,2]. Zinc-finger proteins (ZFPs) are found in yeasts and plants, but their diversity and complexity, notably reflected in the average length of their poly-ZF arrays, have steadily increased during evolution, suggesting that they were involved in speciation and the acquisition of higher functions [1,2,3,4,5]. Paralogous KRAB-ZFP genes exhibit strong signs of positive selection, translating in the accumulation of nonsynonymous mutations at positions encoding for the DNAcontacting residues of their ZFs, indicative of likely species-specific functions and engagement in genetic conflicts, as typically observed for genes encoding effectors of innate immunity [2,5,11,12,13,14]
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