Characterization of the Contradictory Chromatin Signatures at the 3′ Exons of Zinc Finger Genes

Genetics Graduate Group, University of California Davis, Davis, California, United States of America.
PLoS ONE (Impact Factor: 3.23). 02/2011; 6(2):e17121. DOI: 10.1371/journal.pone.0017121
Source: PubMed


The H3K9me3 histone modification is often found at promoter regions, where it functions to repress transcription. However, we have previously shown that 3' exons of zinc finger genes (ZNFs) are marked by high levels of H3K9me3. We have now further investigated this unusual location for H3K9me3 in ZNF genes. Neither bioinformatic nor experimental approaches support the hypothesis that the 3' exons of ZNFs are promoters. We further characterized the histone modifications at the 3' ZNF exons and found that these regions also contain H3K36me3, a mark of transcriptional elongation. A genome-wide analysis of ChIP-seq data revealed that ZNFs constitute the majority of genes that have high levels of both H3K9me3 and H3K36me3. These results suggested the possibility that the ZNF genes may be imprinted, with one allele transcribed and one allele repressed. To test the hypothesis that the contradictory modifications are due to imprinting, we used a SNP analysis of RNA-seq data to demonstrate that both alleles of certain ZNF genes having H3K9me3 and H3K36me3 are transcribed. We next analyzed isolated ZNF 3' exons using stably integrated episomes. We found that although the H3K36me3 mark was lost when the 3' ZNF exon was removed from its natural genomic location, the isolated ZNF 3' exons retained the H3K9me3 mark. Thus, the H3K9me3 mark at ZNF 3' exons does not impede transcription and it is regulated independently of the H3K36me3 mark. Finally, we demonstrate a strong relationship between the number of tandemly repeated domains in the 3' exons and the H3K9me3 mark. We suggest that the H3K9me3 at ZNF 3' exons may function to protect the genome from inappropriate recombination rather than to regulate transcription.

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Available from: Kimberly Blahnik, Oct 05, 2015
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    • "In addition we also observe slight enrichment of repressive marks, especially H3K9me3, at expressed RTSSs. Possible reasons for H3K9me3 enrichment in gene bodies have been described previously [61], but their potential effect on TSSs has to our knowledge not been studied. Our poised RTSSs were selected by quite conservative criteria, but should still make up a representative subset for this category of RTSSs. "
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    ABSTRACT: Deciphering the most common modes by which chromatin regulates transcription, and how this is related to cellular status and processes is an important task for improving our understanding of human cellular biology. The FANTOM5 and ENCODE projects represent two independent large scale efforts to map regulatory and transcriptional features to the human genome. Here we investigate chromatin features around a comprehensive set of transcription start sites in four cell lines by integrating data from these two projects. Transcription start sites can be distinguished by chromatin states defined by specific combinations of both chromatin mark enrichment and the profile shapes of these chromatin marks. The observed patterns can be associated with cellular functions and processes, and they also show association with expression level, location relative to nearby genes, and CpG content. In particular we find a substantial number of repressed inter- and intra-genic transcription start sites enriched for active chromatin marks and Pol II, and these sites are strongly associated with immediate-early response processes and cell signaling. Associations between start sites with similar chromatin patterns are validated by significant correlations in their global expression profiles. The results confirm the link between chromatin state and cellular function for expressed transcripts, and also indicate that active chromatin states at repressed transcripts may poise transcripts for rapid activation during immune response.
    BMC Genomics 03/2014; 15(1):120. DOI:10.1186/1471-2164-15-120 · 3.99 Impact Factor
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    • "Other intriguing studies conducted by Farnham’s group [42, 43] raised some doubts about the currently accepted model of KAP-1 recruitment in the human genome. They showed that at least two mechanisms for recruiting KAP1 may exist, one involving KRAB-ZFPs and another involving other DNA-binding proteins not yet identified. "
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    ABSTRACT: Zinc finger proteins containing the Kruppel associated box (KRAB-ZFPs) constitute the largest individual family of transcriptional repressors encoded by the genomes of higher organisms. KRAB domain, positioned at the NH2 terminus of the KRAB-ZFPs, interacts with a scaffold protein, KAP-1, which is able to recruit various transcriptional factors causing repression of genes to which KRAB ZFPs bind. The relevance of such repression is reflected in the large number of the KRAB zinc finger protein genes in the human genome. However, in spite of their numerical abundance little is currently known about the gene targets and the physiological functions of KRAB- ZFPs. However, emerging evidence links the transcriptional repression mediated by the KRAB-ZFPs to cell proliferation, differentiation, apoptosis and cancer. Moreover, the fact that KRAB containing proteins are vertebrate-specific suggests that they have evolved recently, and that their key roles lie in some aspects of vertebrate development. In this review, we will briefly discuss some regulatory functions of the KRAB-ZFPs in different physiological and pathological states, thus contributing to better understand their biological roles.
    Current Genomics 06/2013; 14(4):268-278. DOI:10.2174/13892029113149990002 · 2.34 Impact Factor
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    • "We began by downloading the sequenced tags for all Kaiso ChIP-seq datasets from the UCSC browser (from the ENCODE consortium); two replicate Bowtie-mapped ChIP-seq datasets were downloaded for GM12878, K562, A549, HepG2, HCT116, and SK-N-SH cells. Peaks were called for each replicate in each cell type using Sole-Search [11,12]; see Table 1. To determine the reproducibility of the data, an overlap analysis was performed by truncating both replicates to the same peak number and comparing the top 40% of replicate 1 to the entire set of peaks of replicate 2 (and vice versa, which is indicated as the reciprocal overlap in Table 1). "
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    ABSTRACT: Background DNA methylation and repressive histone modifications cooperate to silence promoters. One mechanism by which regions of methylated DNA could acquire repressive histone modifications is via methyl DNA-binding transcription factors. The zinc finger protein ZBTB33 (also known as Kaiso) has been shown in vitro to bind preferentially to methylated DNA and to interact with the SMRT/NCoR histone deacetylase complexes. We have performed bioinformatic analyses of Kaiso ChIP-seq and DNA methylation datasets to test a model whereby binding of Kaiso to methylated CpGs leads to loss of acetylated histones at target promoters. Results Our results suggest that, contrary to expectations, Kaiso does not bind to methylated DNA in vivo but instead binds to highly active promoters that are marked with high levels of acetylated histones. In addition, our studies suggest that DNA methylation and nucleosome occupancy patterns restrict access of Kaiso to potential binding sites and influence cell type-specific binding. Conclusions We propose a new model for the genome-wide binding and function of Kaiso whereby Kaiso binds to unmethylated regulatory regions and contributes to the active state of target promoters.
    Epigenetics & Chromatin 05/2013; 6(1):13. DOI:10.1186/1756-8935-6-13 · 5.33 Impact Factor
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