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      The Evolution of Epigenetic Regulators CTCF and BORIS/CTCFL in Amniotes

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      PLoS Genetics

      Public Library of Science

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          Abstract

          CTCF is an essential, ubiquitously expressed DNA-binding protein responsible for insulator function, nuclear architecture, and transcriptional control within vertebrates. The gene CTCF was proposed to have duplicated in early mammals, giving rise to a paralogue called “brother of regulator of imprinted sites” ( BORIS or CTCFL) with DNA binding capabilities similar to CTCF, but testis-specific expression in humans and mice. CTCF and BORIS have opposite regulatory effects on human cancer-testis genes, the anti-apoptotic BAG1 gene, the insulin-like growth factor 2/H19 imprint control region ( IGF2/H19 ICR), and show mutually exclusive expression in humans and mice, suggesting that they are antagonistic epigenetic regulators. We discovered orthologues of BORIS in at least two reptilian species and found traces of its sequence in the chicken genome, implying that the duplication giving rise to BORIS occurred much earlier than previously thought. We analysed the expression of CTCF and BORIS in a range of amniotes by conventional and quantitative PCR. BORIS, as well as CTCF, was found widely expressed in monotremes (platypus) and reptiles (bearded dragon), suggesting redundancy or cooperation between these genes in a common amniote ancestor. However, we discovered that BORIS expression was gonad-specific in marsupials (tammar wallaby) and eutherians (cattle), implying that a functional change occurred in BORIS during the early evolution of therian mammals. Since therians show imprinting of IGF2 but other vertebrate taxa do not, we speculate that CTCF and BORIS evolved specialised functions along with the evolution of imprinting at this and other loci, coinciding with the restriction of BORIS expression to the germline and potential antagonism with CTCF.

          Author Summary

          Epigenetic mechanisms heritably change gene expression without altering DNA sequence. Currently, little is known about the evolution of epigenetic traits, and the genes that control them. CTCF is an essential epigenetic regulator that is expressed widely in the tissues of vertebrates and modifies the transcription of genes by altering their location within the nucleus. CTCF duplicated at some time during vertebrate evolution, giving rise to a similar gene called BORIS with expression that is limited to parts of the testes of humans and mice, but whose function is largely unknown. BORIS may contribute to the regulation of genomic imprinting, a form of epigenetic control specific to live-bearing mammals. We discovered BORIS in all mammal groups and reptiles, implying that its genesis from CTCF occurred much earlier than previously thought, preceding genomic imprinting by over 100 million years. CTCF and BORIS have not previously been found expressed together except in tumours, leading to the hypothesis that CTCF and BORIS have conflicting functions that cause cancer when allowed to overlap. We found that CTCF and BORIS are expressed alongside each other in multiple somatic and reproductive tissues of a reptile (bearded dragon) and an egg-laying mammal (platypus), but that BORIS is restricted to the gonads of live-bearing mammals (cattle and wallaby). This indicates that BORIS specialised during mammalian evolution, in concert with the evolution of genomic imprinting.

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          Most cited references 68

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          A new approach to rapid sequence comparison, basic local alignment search tool (BLAST), directly approximates alignments that optimize a measure of local similarity, the maximal segment pair (MSP) score. Recent mathematical results on the stochastic properties of MSP scores allow an analysis of the performance of this method as well as the statistical significance of alignments it generates. The basic algorithm is simple and robust; it can be implemented in a number of ways and applied in a variety of contexts including straightforward DNA and protein sequence database searches, motif searches, gene identification searches, and in the analysis of multiple regions of similarity in long DNA sequences. In addition to its flexibility and tractability to mathematical analysis, BLAST is an order of magnitude faster than existing sequence comparison tools of comparable sensitivity.
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            High-resolution profiling of histone methylations in the human genome.

            Histone modifications are implicated in influencing gene expression. We have generated high-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology. Typical patterns of histone methylations exhibited at promoters, insulators, enhancers, and transcribed regions are identified. The monomethylations of H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations of H3K27, H3K9, and H3K79 are linked to repression. H2A.Z associates with functional regulatory elements, and CTCF marks boundaries of histone methylation domains. Chromosome banding patterns are correlated with unique patterns of histone modifications. Chromosome breakpoints detected in T cell cancers frequently reside in chromatin regions associated with H3K4 methylations. Our data provide new insights into the function of histone methylation and chromatin organization in genome function.
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              Cancer/testis (CT) antigens, of which more than 40 have now been identified, are encoded by genes that are normally expressed only in the human germ line, but are also expressed in various tumour types, including melanoma, and carcinomas of the bladder, lung and liver. These immunogenic proteins are being vigorously pursued as targets for therapeutic cancer vaccines. CT antigens are also being evaluated for their role in oncogenesis--recapitulation of portions of the germline gene-expression programme might contribute characteristic features to the neoplastic phenotype, including immortality, invasiveness, immune evasion, hypomethylation and metastatic capacity.
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                Author and article information

                Affiliations
                ARC Centre for Kangaroo Genomics, Research School of Biological Sciences, The Australian National University, Canberra, Australian Capital Territory, Australia
                University of Cambridge, United Kingdom
                Author notes

                Conceived and designed the experiments: TAH. Performed the experiments: TAH. Analyzed the data: TAH JED JAMG. Wrote the paper: TAH JAMG.

                Contributors
                Role: Editor
                Journal
                PLoS Genet
                plos
                plosgen
                PLoS Genetics
                Public Library of Science (San Francisco, USA )
                1553-7390
                1553-7404
                August 2008
                August 2008
                29 August 2008
                : 4
                : 8
                2515639
                18769711
                08-PLGE-RA-0387R2
                10.1371/journal.pgen.1000169
                (Editor)
                Hore et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Counts
                Pages: 11
                Categories
                Research Article
                Evolutionary Biology/Evolutionary and Comparative Genetics
                Genetics and Genomics/Comparative Genomics
                Genetics and Genomics/Epigenetics
                Genetics and Genomics/Medical Genetics
                Oncology

                Genetics

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