Expansion and diversification of KRAB zinc-finger genes within a cluster including Regulator of sex-limitation 1 and 2

Krebs, Christopher J.; Larkins, Leslie K.; Khan, Shaema; Robins, Diane M.

doi:10.1016/j.ygeno.2005.03.004

Cited by 41 publications

(44 citation statements)

References 26 publications

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“…Evolutionary divergence within the zinc finger array of paralogous genes can lead to diversification of gene copies (Looman et al 2002;Hamilton et al 2003;Shannon et al 2003;Krebs et al 2005); data presented here show that these changes can occur very rapidly, serving to distinguish DNA-binding domains of even very recent duplicates. In the ZNF91 subfamily, we found few examples of KRAB-ZNF paralogs that have retained the same number, arrangement, or sequence of zinc finger motifs.…”

Section: Discussionmentioning

confidence: 79%

“…Most KRAB-ZNF genes reside in large familial clusters, many of which contain substantial numbers of lineage-specific genes. Studies focused on specific subfamilies have shown that paralogs typically diverge through structural changes within the ZNF arrays that are likely to affect DNAbinding properties and, potentially, target choice for the duplicated transcription factors (Looman et al 2002;Hamilton et al 2003;Shannon et al 2003;Krebs et al 2005).…”

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confidence: 99%

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Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes

et al. 2006

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Most genes are conserved in mammals, but certain gene families have acquired large numbers of lineage-specific loci through repeated rounds of gene duplication, divergence, and loss that have continued in each mammalian group. One such family encodes KRAB-zinc finger (KRAB-ZNF) proteins, which function as transcriptional repressors. One particular subfamily of KRAB-ZNF genes, including ZNF91, has expanded specifically in primates to comprise more than 110 loci in the human genome. Genes of the ZNF91 subfamily reside in large gene clusters near centromeric regions of human chromosomes 19 and 7 with smaller clusters or isolated copies in other locations. Phylogenetic analysis indicates that many of these genes arose before the split between the New and Old World monkeys, but the ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans. Paralogous loci are distinguished by divergence within their zinc finger arrays, indicating selection for proteins with different regulatory targets. In addition, many loci produce multiple alternatively spliced transcripts encoding proteins that may serve separate and perhaps even opposing regulatory roles because of the modular motif structure of KRAB-ZNF genes. The tissue-specific expression patterns and rapid structural divergence of ZNF91 subfamily genes suggest a role in determining gene expression differences between species and the evolution of novel primate traits.

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Section: Discussionmentioning

confidence: 79%

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confidence: 99%

Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes

et al. 2006

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“…Analysis of the human genome sequence revealed 423 independent KRAB-zinc finger protein (KRAB-zfp)-coding loci, yielding alternative transcripts that altogether predict at least 742 structurally distinct proteins (23). Comparative ge-nome analyses indicate that this gene family is vertebrate specific and that the repertoire of KRAB-zfps differs significantly between species, suggesting that KRAB-zfps may regulate programs of gene expression that contribute to speciation (16,29). The KRAB domain, defined by approximately 75 amino acids, is a transferable module that possesses DNA binding-dependent transcriptional repression activity.…”

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confidence: 99%

The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression

Sripathy

Stevens

Schultz

2006

Molecular and Cellular Biology

290

263

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KAP1/TIF1␤ is proposed to be a universal corepressor protein for the KRAB zinc finger protein (KRAB-zfp) superfamily of transcriptional repressors. To characterize the role of KAP1 and KAP1-interacting proteins in transcriptional repression, we investigated the regulation of stably integrated reporter transgenes by hormoneresponsive KRAB and KAP1 repressor proteins. Here, we demonstrate that depletion of endogenous KAP1 levels by small interfering RNA (siRNA) significantly inhibited KRAB-mediated transcriptional repression of a chromatin template. Similarly, reduction in cellular levels of HP1␣/␤/␥ and SETDB1 by siRNA attenuated KRAB-KAP1 repression. We also found that direct tethering of KAP1 to DNA was sufficient to repress transcription of an integrated transgene. This activity is absolutely dependent upon the interaction of KAP1 with HP1 and on an intact PHD finger and bromodomain of KAP1, suggesting that these domains function cooperatively in transcriptional corepression. The achievement of the repressed state by wild-type KAP1 involves decreased recruitment of RNA polymerase II, reduced levels of histone H3 K9 acetylation and H3K4 methylation, an increase in histone occupancy, enrichment of trimethyl histone H3K9, H3K36, and histone H4K20, and HP1 deposition at proximal regulatory sequences of the transgene. A KAP1 protein containing a mutation of the HP1 binding domain failed to induce any change in the histone modifications associated with DNA sequences of the transgene, implying that HP1-directed nuclear compartmentalization is required for transcriptional repression by the KRAB/KAP1 repression complex. The combination of these data suggests that KAP1 functions to coordinate activities that dynamically regulate changes in histone modifications and deposition of HP1 to establish a de novo microenvironment of heterochromatin, which is required for repression of gene transcription by KRAB-zfps.Genetic and epigenetic programs that control proper spatial and temporal patterns of gene expression are instrumental for pluripotent stem cells to determine cellular identity and maintain homeostasis of adult metazoans. Though historically viewed as a passive packaging unit, remodeling of chromatin structure has emerged as a key target for programming of gene expression during early embryogenesis and tissue-specific gene transcription. The dynamic regulation of chromatin organization appears to be accomplished in part by at least four families of proteins, including the following: (i) macromolecular protein complexes that utilize energy from ATP hydrolysis to disrupt DNA-protein interactions; (ii) proteins with intrinsic enzymatic activity to posttranslationally modify the core histones; (iii) nonhistone chromosomal proteins; and (iv) histone variants. Increasing experimental evidence indicates that the combinatorial use of histone variants, posttranslational modification of histones (i.e., acetylation, phosphorylation, ubiquitination, and methylation), and nonhistone chromatin-associated proteins that recognize th...

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“…For the vast majority of these, nothing is known about their target-gene repertoire or binding motif. A few, studied in more detail, play important roles in diverse cellular and organismic functions ranging from regulation of rodent male-specific genes by the Rsl (regulator of sex limitation) Krab repressors (Krebs et al 2005) to lipid metabolism and possible predisposition to hypoalphalipoproteinemia by znf202 (Wagner et al 2000). Much more is known about NRSF/REST, a zinc finger repressor famous for negative regulation of neuronal genes in non-neuronal cell types and in neuronal stem cells and progenitors prior to differentiation (Chong et al 1995;Schoenherr and Anderson 1995;Chen et al 1998).…”

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confidence: 99%

Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoire

Mortazavi

Thompson²,

Garcia³

et al. 2006

Genome Res.

152

157

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We constructed and applied an open source informatic framework called Cistematic in an effort to predict the target gene repertoire for transcription factors with large binding sites. Cistematic uses two different evolutionary conservation-filtering algorithms in conjunction with several analysis modules. Beginning with a single conserved and biologically tested site for the neuronal repressor NRSF/REST, Cistematic generated a refined PSFM (position specific frequency matrix) based on conserved site occurrences in mouse, human, and dog genomes. Predictions from this model were validated by chromatin immunoprecipitation (ChIP) followed by quantitative PCR. The combination of transfection assays and ChIP enrichment data provided an objective basis for setting a threshold for membership and rank-ordering a final gene cohort model consisting of 842 high-confidence sites in the human genome associated with 733 genes. Statistically significant enrichment of NRSE-associated genes was found for neuron-specific Gene Ontology (GO) terms and neuronal mRNA expression profiles. A more extensive evolutionary survey showed that NRSE sites matching the PSFM model exist in roughly similar numbers in all fully sequenced vertebrate genomes but are notably absent from invertebrate and protochordate genomes, as is NRSF itself. Some NRSF/REST sites reside in repeats, which suggests a mechanism for both ancient and modern dispersal of NRSEs through vertebrate genomes. Multiple predicted sites are located near neuronal microRNA and splicing-factor genes, and these tested positive for NRSF/REST occupancy in vivo. The resulting network model integrates post-transcriptional and translational controllers, including candidate feedback loops on NRSF and its corepressor, CoREST.

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Expansion and diversification of KRAB zinc-finger genes within a cluster including Regulator of sex-limitation 1 and 2

Cited by 41 publications

References 26 publications

Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes

Evolutionary expansion and divergence in the ZNF91 subfamily of primate-specific zinc finger genes

The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression

Comparative genomics modeling of the NRSF/REST repressor network: From single conserved sites to genome-wide repertoire

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