A comprehensive catalog of human KRAB-associated zinc finger genes: Insights into the evolutionary history of a large family of transcriptional repressors

Abstract

Krüppel-type zinc finger (ZNF) motifs are prevalent components of transcription factor proteins in all eukaryotes. KRAB-ZNF proteins, in which a potent repressor domain is attached to a tandem array of DNA-binding zinc-finger motifs, are specific to tetrapod vertebrates and represent the largest class of ZNF proteins in mammals. To define the full repertoire of human KRAB-ZNF proteins, we searched the genome sequence for key motifs and then constructed and manually curated gene models incorporating those sequences. The resulting gene catalog contains 423 KRAB-ZNF protein-coding loci, yielding alternative transcripts that altogether predict at least 742 structurally distinct proteins. Active rounds of segmental duplication, involving single genes or larger regions and including both tandem and distributed duplication events, have driven the expansion of this mammalian gene family. Comparisons between the human genes and ZNF loci mined from the draft mouse, dog, and chimpanzee genomes not only identified 103 KRAB-ZNF genes that are conserved in mammals but also highlighted a substantial level of lineage-specific change; at least 136 KRAB-ZNF coding genes are primate specific, including many recent duplicates. KRAB-ZNF genes are widely expressed and clustered genes are typically not coregulated, indicating that paralogs have evolved to fill roles in many different biological processes. To facilitate further study, we have developed a Web-based public resource with access to gene models, sequences, and other data, including visualization tools to provide genomic context and interaction with other public data sets.

Widespread establishment and regulatory impact of Alu exons in human genes

“…We collected a list of 551 UCSC Known Genes loci encoding ZNF transcription factors, using a catalog of ZNF genes compiled by Huntley et al (26). Specifically, we intersected the ZNF genes in Huntley et al with the UCSC Known Genes annotations, with the requirement that at least 70% of the genomic region of a ZNF gene defined by Huntley et al be covered by a UCSC Known Genes transcript.…”

A Novel 19q13 Nucleolar Zinc Finger Protein Suppresses Tumor Cell Growth through Inhibiting Ribosome Biogenesis and Inducing Apoptosis but Is Frequently Silenced in Multiple Carcinomas

“…Other clusters are usually found in centromeric and telomeric regions of chromosomes. This phenomenon is conserved in other species as well, suggesting that KRAB-ZFPs are functionally important during evolution (6)(7)(8). The biological functions of KRAB-ZFPs are important to the regulation of cell proliferation, differentiation, apoptosis, and neoplastic transformation (7).…”

“…Some ZFPs function as oncogenic proteins such as ZNF217 and ZNF639 (1,2), whereas others can act as tumor suppressors, such as ZAC, ST18, and ZNF382 (3)(4)(5). ZFPs bind to promoters with their zinc finger domains and activate or repress gene expression through their association proteins (1,6). About one-third of the ZFPs are Kr€ uppel-associated box containing zinc finger proteins (KRAB-ZFP).…”

ZNF552, a novel human KRAB/C2H2 zinc finger protein, inhibits AP-1- and SRE-mediated transcriptional activity

“…In addition to zinc finger regions, most of these proteins also contain a regulatory domain, the Kruppel-associated box (KRAB). The KRAB domain consists of an A box and a B box encoded by two separate exons (9). Members of the Kruppel-like zinc finger family can function as activators and/or repressors of gene transcription and regulate embryonic development as well as a variety of physiological processes in the adult (10).…”