The Most Redundant Sequences in Human CpG Island Library Are Derived from Mitochondrial Genome

An altered pattern of epigenetic modifications, such as DNA methylation and histone modification, is critical to many common human diseases, including cancer. Recently, mitochondrial DNA (mtDNA) was reported to be associated with tumorigenesis through epigenetic regulation of methylation patterns. One of the promising approaches to study DNA methylation and CpG islands (CGIs) is sequencing and analysis of clones derived from the physical library generated by methyl-CpG-binding domain proteins and restriction enzyme MseI. In this study, we observed that the most redundant sequences of 349 clones in a human CGI library were all generated from the human mitochondrial genome. Further analysis indicated that there was a 5,845-bp DNA transfer from mtDNA to chromosome 1, and all the clones should be the products of a 510-bp MseI fragment, which contained a putative CGI of 270 bp. The 510-bp fragment was annotated as part of cytochrome c oxidase subunit II (COXII), and phylogenetic analysis of homologous sequences containing COXII showed three DNA transfer events from mtDNA to nuclear genome, one of which underwent secondary transfer events between different chromosomes. These results may further our understanding of how the mtDNA regulates DNA methylation in the nucleus.

[1]  M. Esteller.  Cancer epigenomics: DNA methylomes and histone-modification maps , 2007, Nature Reviews Genetics.

[2]  Igor Jurisica,et al.  CpG Island microarray probe sequences derived from a physical library are representative of CpG Islands annotated on the human genome , 2005, Nucleic acids research.

[3]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[4]  Chun-Yang Fan,et al.  Mitochondrial regulation of cancer associated nuclear DNA methylation. , 2007, Biochemical and biophysical research communications.

[5]  A. Bird,et al.  Methylation-Induced Repression— Belts, Braces, and Chromatin , 1999, Cell.

[6]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[7]  Kokichi Sugano,et al.  Methylation of mitochondrial DNA is not a useful marker for cancer detection. , 2004, Clinical chemistry.

[8]  Jose V. Lopez,et al.  Numt, a recent transfer and tandem amplification of mitochondrial DNA to the nuclear genome of the domestic cat , 1994, Journal of Molecular Evolution.

[9]  M. Frommer,et al.  CpG islands in vertebrate genomes. , 1987, Journal of molecular biology.

[10]  W. Reik,et al.  Genomic imprinting: parental influence on the genome , 2001, Nature Reviews Genetics.

[11]  A. Razin,et al.  Methylation of CpG sequences in eukaryotic DNA , 1981, FEBS letters.

[12]  A. Bird,et al.  Use of restriction enzymes to study eukaryotic DNA methylation: II. The symmetry of methylated sites supports semi-conservative copying of the methylation pattern. , 1978, Journal of molecular biology.

[13]  A. Bird,et al.  Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals , 2003, Nature Genetics.

[14]  Rudolf Jaenisch,et al.  Targeted mutation of the DNA methyltransferase gene results in embryonic lethality , 1992, Cell.

[15]  Daiya Takai,et al.  Comprehensive analysis of CpG islands in human chromosomes 21 and 22 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Dario Leister,et al.  NUMTs in sequenced eukaryotic genomes. , 2004, Molecular biology and evolution.

[17]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[18]  Daiya Takai,et al.  The CpG Island Searcher: A new WWW resource , 2003, Silico Biol..

[19]  C. Walsh,et al.  Cytosine methylation and mammalian development. , 1999, Genes & development.

[20]  Jiajie Zhang,et al.  MethyCancer: the database of human DNA methylation and cancer , 2007, Nucleic Acids Res..

[21]  Susan J Clark,et al.  DNA methylation and gene silencing in cancer: which is the guilty party? , 2002, Oncogene.

[22]  Sudhir Kumar,et al.  MEGA3: Integrated software for Molecular Evolutionary Genetics Analysis and sequence alignment , 2004, Briefings Bioinform..

[23]  D. Smiraglia,et al.  A novel role for mitochondria in regulating epigenetic modifications in the nucleus , 2008, Cancer biology & therapy.

[24]  S. Cross,et al.  Purification of CpG islands using a methylated DNA binding column , 1994, Nature Genetics.

[25]  Julie D Thompson,et al.  Multiple Sequence Alignment Using ClustalW and ClustalX , 2003, Current protocols in bioinformatics.

[26]  Philippe Dessen,et al.  Structure and chromosomal distribution of human mitochondrial pseudogenes. , 2002, Genomics.

[27]  Peter A. Jones,et al.  The Epigenomics of Cancer , 2007, Cell.

[28]  Hong Duan,et al.  Role for DNA methylation in the control of cell type–specific maspin expression , 2002, Nature Genetics.

[29]  M. Surani,et al.  Imprinting and the Epigenetic Asymmetry Between Parental Genomes , 2001, Science.

[30]  A. Bird.  CpG-rich islands and the function of DNA methylation , 1986, Nature.

[31]  S. Cross,et al.  Isolation of CpG islands from large genomic clones. , 1999, Nucleic acids research.

[32]  H. Cedar,et al.  Linking DNA methylation and histone modification: patterns and paradigms , 2009, Nature Reviews Genetics.