A comprehensive catalog of human KRAB-associated zinc finger genes: Insights into the evolutionary history of a large family of transcriptional repressors (original) (raw)
Related papers
Molecular Biology and Evolution, 2010
Recent segmental duplications (SDs), arising from duplication events that occurred within the past 35-40 My, have provided a major resource for the evolution of proteins with primate-specific functions. KRAB zinc finger (KRAB-ZNF) transcription factor genes are overrepresented among genes contained within these recent human SDs. Here, we examine the structural and functional diversity of the 70 human KRAB-ZNF genes involved in the most recent primate SD events including genes that arose in the hominid lineage. Despite their recent advent, many parent-daughter KRAB-ZNF gene pairs display significant differences in zinc finger structure and sequence, expression, and splicing patterns, each of which could significantly alter the regulatory functions of the paralogous genes. Paralogs that emerged on the lineage to humans and chimpanzees have undergone more evolutionary changes per unit of time than genes already present in the common ancestor of rhesus macaques and great apes. Taken together, these data indicate that a substantial fraction of the recently evolved primate-specific KRAB-ZNF gene duplicates have acquired novel functions that may possibly define novel regulatory pathways and suggest an active ongoing selection for regulatory diversity in primates.
Deep Vertebrate Roots for Mammalian Zinc Finger Transcription Factor Subfamilies
Genome Biology and Evolution, 2014
While many vertebrate transcription factor (TF) families are conserved, the C2H2 zinc finger (ZNF) family stands out as a notable exception. In particular, novel ZNF gene types have arisen, duplicated, and diverged independently throughout evolution to yield many lineage-specific TF genes. This evolutionary dynamic not only raises many intriguing questions but also severely complicates identification of those ZNF genes that remain functionally conserved. To address this problem, we searched for vertebrate "DNA binding orthologs" by mining ZNF loci from eight sequenced genomes and then aligning the patterns of DNA-binding amino acids, or "fingerprints," extracted from the encoded ZNF motifs. Using this approach, we found hundreds of lineage-specific genes in each species and also hundreds of orthologous groups. Most groups of orthologs displayed some degree of fingerprint divergence between species, but 174 groups showed fingerprint patterns that have been very rigidly conserved. Focusing on the dynamic KRAB-ZNF subfamily-including nearly 400 human genes thought to possess potent KRAB-mediated epigenetic silencing activitieswe found only three genes conserved between mammals and nonmammalian groups. These three genes, members of an ancient familial cluster, encode an unusual KRAB domain that functions as a transcriptional activator. Evolutionary analysis confirms the ancient provenance of this activating KRAB and reveals the independent expansion of KRAB-ZNFs in every vertebrate lineage. Most human ZNF genes, from the most deeply conserved to the primate-specific genes, are highly expressed in immune and reproductive tissues, indicating that they have been enlisted to regulate evolutionarily divergent biological traits.
Genome Research, 2003
Mammalian genomes carry hundreds of Krüppel-type zinc finger (ZNF) genes, most of which reside in familial clusters. ZNF genes encoding Krüppel-associated box (KRAB) motifs are especially prone to this type of tandem organization. Despite their prevalence, little is known about the functions or evolutionary histories of these clustered gene families. Here we describe a homologous pair of human and mouse KRAB-ZNF gene clusters containing 21 human and 10 mouse genes, respectively. Evolutionary analysis uncovered only three pairs of putative orthologs and two cases where a single gene in one species is related to multiple genes in the other; several human genes have no obvious homolog in mouse. We deduce that duplication and loss of ancestral cluster members occurred independently in the primate and rodent lineages after divergence, yielding substantially different ZNF gene repertoires in humans and mice. Differences in expression patterns and sequence divergence within the DNA binding regions of predicted proteins suggest that the duplicated genes have acquired novel functions over evolutionary time. Since KRAB-ZNF proteins are predicted to function as transcriptional regulators, the elaboration of new lineage-specific genes in this and other clustered ZNF families is likely to have had a significant impact on species-specific aspects of biology.
Genomics, 1998
tion factors and have been shown in a few instances to Genetic and physical mapping studies indicate that affect cell proliferation and/or development (El-Baradi hundreds of zinc-finger (ZNF)-containing genes popuand Pieler, 1991, and references therein). Many, but late the human genome and that many of these genes apparently not all, of the Kruppel-type ZNF proteins are arranged in familial clusters. However, the extent contain conserved modules in addition to their zinc to which these tandemly arrayed families are confingers that are hypothesized to be involved in proteinserved among mammalian species is largely unknown. protein interactions associated with transcription con-In a previous study, we identified a conserved cluster trol. A non-ZNF motif frequently found in combination of Kruppel-associated box (KRAB)-containing ZNF with zinc fingers is the Kruppel-associated box (KRAB), genes located near the XRCC1 gene in human chromowhich is located at the N-terminus of approximately some 19q13.2 and mouse chromosome 7 and analyzed one-third of the mammalian C2H2-type ZNF proteins two members of the murine gene family, Zfp93 and . This element may be composed Zfp94, in detail. Here we report the identification and of a single A domain or, alternatively, of A and B docharacterization of putative human orthologs of these mains (Constantinou-Deltas et al., 1992; Bellefroid et murine genes. The human genes ZFP93 and ZNF45 are al., 1993). Several studies have demonstrated that the substantially similar to their murine counterparts in KRAB motif acts as a repressor of both activated and overall structure, but two notable differences exist bebasal transcription (Margolin et al., 1994; Witzgall et tween the sets of genes. First, the human genes encode Pengue and Lania, 1996) and that repression more ZNF repeats than their murine counterparts.
2013
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...
Journal of Biological Chemistry, 1998
We have identified a novel zinc finger protein that has been named ubiquitous Krü ppel-like factor (UKLF) based on structural considerations and the pattern of gene expression. UKLF was isolated by the polymerase chain reaction approach using degenerate oligonucleotides corresponding to the DNA-binding domain of erythroid Krü ppel-like factor (EKLF) and cDNA prepared from human vascular endothelial cells. The carboxyl-terminal portion of UKLF contains three zinc fingers of the Cys 2-His 2 type and binds in vitro to the CACCC motif of the -globin promoter and to the Sp1 recognition sequence. The amino-terminal portion of UKLF consists of a hydrophobic region rich in serines and a negatively charged segment with several glutamic acid residues. The first 47 amino acids of the acidic region are nearly identical to the amino-terminal portion of another Krü ppel-like factor, the so-called core promoter-binding protein (CPBP) or Zf9. Like CPBP/ Zf9, UKLF can function as a transcription activator in co-transfection assays. However, this activity is lost when the highly conserved amino-terminal segment is deleted. These findings indicate that UKLF and CPBP/ Zf9 represent a distinct subgroup of closely related Krü ppel-like activators of transcription. Mapping of the UKLF gene to chromosome 2 suggested that UKLF and CPBP/Zf9 translocated to different chromosomes following duplication from an ancestral gene.
PLoS ONE, 2011
The molecular changes underlying major phenotypic differences between humans and other primates are not well understood, but alterations in gene regulation are likely to play a major role. Here we performed a thorough evolutionary analysis of the largest family of primate transcription factors, the Krüppel-type zinc finger (KZNF) gene family. We identified and curated gene and pseudogene models for KZNFs in three primate species, chimpanzee, orangutan and rhesus macaque, to allow for a comparison with the curated set of human KZNFs. We show that the recent evolutionary history of primate KZNFs has been complex, including many lineage-specific duplications and deletions. We found 213 speciesspecific KZNFs, among them 7 human-specific and 23 chimpanzee-specific genes. Two human-specific genes were validated experimentally. Ten genes have been lost in humans and 13 in chimpanzees, either through deletion or pseudogenization. We also identified 30 KZNF orthologs with human-specific and 42 with chimpanzee-specific sequence changes that are predicted to affect DNA binding properties of the proteins. Eleven of these genes show signatures of accelerated evolution, suggesting positive selection between humans and chimpanzees. During primate evolution the most extensive re-shaping of the KZNF repertoire, including most gene additions, pseudogenizations, and structural changes occurred within the subfamily homininae. Using zinc finger (ZNF) binding predictions, we suggest potential impact these changes have had on human gene regulatory networks. The large species differences in this family of TFs stands in stark contrast to the overall high conservation of primate genomes and potentially represents a potent driver of primate evolution.
Characterization and mapping of human genes encoding zinc finger proteins
Proceedings of the National Academy of Sciences, 1991
The zinc finger motif, exemplified by a segment of the Drosophila gap gene Krfippel, is a nudeic add-binding domain present in many transcription factors. To investigate the gene family encoding this motif in the human genome, a placental genomic library was screened at moderate stringency with a degenerate oligodeoxynucleotide probe designed to hybridize to the His/Cys (H/C) link region between adjoining zinc fingers.