- Email: [email protected]
DNA methylation: Molecular biology and biological significance
Cell, Vol. 73, 429, May 7, 1993, Copyright 0 1993 by Cell Press
Book Review
DNA Methylation: A Matter for Envy by Those with Small Genomes DNA Methylation: Molecular Biology and Biological Significance. Edited by J. P. Jost and H. P. Saluz. Basel: Birkhauser (1993). 572 pp. $139.50.
A prominent geneticist at my institution has been noted to say that DNA methylation must not be important because Caenorhabditis elegans doesn’t have it. This opinion represents one border of a field that extends to the premise that 5-methylcytosine (m5C) has a crucial role, in effect expanding the functional components of DNA to five nucleotides and directing stable reproducible patterns in the organization of higher eukaryotic genomes. In such genomes, the importance of m5C is tightly linked to the structure of chromatin and to the profound effects that chromatin structure has on gene expression. Debate, illustrated by the two extremes in opinion, has been over whether m5C is a major player directing the organization of chromatin, or whether it is a bit player whose presence is more decorative than crucial. One suggestion, made to reconcile the absence of m5C in lower eukaryotic genomes with its potential importance, is that higher eukaryotes must have m5C to compensate for their larger genomes-that m5C is necessary to compartmentalize them into repressed and more manageable active domains(Bestor, Phil. Trans. Ft. Sot. Lond. 326,179-187, 1990). Perhaps also there is a correlation with the fact that these animals and plants require permanent populations of stem cells in many tissues during the long lives of the organisms. Caenorhabditis should be so fortunate. Most readersof this bookwill come from a background in vertebrate systems, where the field has progressed most rapidly, and it is this group who should recognize its impact. It has become apparent that cytosine methylation is “cleared” at the time of fertilization, only to be fully reestablished by the time of implantation. Thus, active demethylation occurs, and complex patterns of methylation can be reproducibly established de novo. The importance of these effects is signaled by the discovery that mouse embryos carrying a homozygous mutation in the unique methyltransferase gene that lowers its level of expression to about 30% of wild type are not viable after the time of implantation (Li et al., Cell 69, 915-926, 1992). The inference is that an incompletely methylated genome cannot properly direct the complex repertoire of embryonic development, although one cannot exclude the possibility that methyltransferase has other essential functions. Two additional recent discoveries tighten the association of m5C with key biological processes. First, endogenous genes have been identified whose methylation patterns correlate with parental imprinting (pp. 481-482):
imprinted genes are only expressed when inherited from one particular parent. Since the patterns of methylation in various sequence elements differ between the mature sperm and the mature oocyte (pp. 343-350), it is tempting to attribute imprinting directly to methylation itself. Second, it is now clear that a predominance of inactivating mutations of the ~53 tumor suppressor gene in some human cancers are due to transitions resulting from deamination of m5C to T (Jones et al., Bioessays 74, 33-36, 1992; this volume, pp. 497-502). Indeed, methyltransferase itself may enzymatically deaminate cytosine under certain circumstances (Shen et al., Cell 77, 1073-1080, 1992). These examples serve to illustrate that we may not yet know why m5C is important in vertebrates but it is, and the field is poised to provide more answers about its functions. In this regard, this publication is timely and up-todate and provides a comprehensive background not available in other single sources. It covers the subject from methods to analyze methylation, to methytransferase, to methylation effects on DNA structure, to m5C-binding proteins and chromatin structure, to methylation patterns during development, and to methylation effects on expression of the best-studied gene and viral systems. The completeness is particularly valuable for those with limited knowledge of the field. For example, it is very helpful to have in one place separate presentations of data describing the different m5C-binding proteins that have been characterized to date. My discussion so far has centered on methylation in vertebrate systems because most readers are likely to work in that area. However, other systems are not neglected. In fact, reviews of prokaryotic, algal, fungal, and plant methylation preceding the vertebrate sections are important in their own right and provide a necessary perspective to the field. The particularly comprehensive chapter on m5C in plants will serve as an important reference source for plant biologists. The only gap in this volume concerns N6-methyldeoxyadenosine in eukaryotes. In ciliated protozoans, such as Tetrahymena thermophila, N6methyldeoxyadenosine is specific for macronuclear DNA and serves to distinguish specific molecular forms that are retained in that structure (e.g., Blackburn et al., Nucl. Acids Res. 11, 5131-5145, 1983; Capowski et al., Mol. Cell. Biol. 9,2598-2605,1989). There are also recent indications that NG-methyldeoxyadenosine has functional effects in plants. Given that the focus of this volume is on m5C, the omission of a chapter on NB-methyldeoxyadenosine is, perhaps, understandable. I got my copy of this book free. After reading it, I appreciate what a bargain that was. It belongs on my shelf and I would pay the price to put it there. It is so recommended. John C. Rogers Department of Biology Washington University St. Louis, Missouri 63130
Book Review
DNA Methylation: A Matter for Envy by Those with Small Genomes DNA Methylation: Molecular Biology and Biological Significance. Edited by J. P. Jost and H. P. Saluz. Basel: Birkhauser (1993). 572 pp. $139.50.
A prominent geneticist at my institution has been noted to say that DNA methylation must not be important because Caenorhabditis elegans doesn’t have it. This opinion represents one border of a field that extends to the premise that 5-methylcytosine (m5C) has a crucial role, in effect expanding the functional components of DNA to five nucleotides and directing stable reproducible patterns in the organization of higher eukaryotic genomes. In such genomes, the importance of m5C is tightly linked to the structure of chromatin and to the profound effects that chromatin structure has on gene expression. Debate, illustrated by the two extremes in opinion, has been over whether m5C is a major player directing the organization of chromatin, or whether it is a bit player whose presence is more decorative than crucial. One suggestion, made to reconcile the absence of m5C in lower eukaryotic genomes with its potential importance, is that higher eukaryotes must have m5C to compensate for their larger genomes-that m5C is necessary to compartmentalize them into repressed and more manageable active domains(Bestor, Phil. Trans. Ft. Sot. Lond. 326,179-187, 1990). Perhaps also there is a correlation with the fact that these animals and plants require permanent populations of stem cells in many tissues during the long lives of the organisms. Caenorhabditis should be so fortunate. Most readersof this bookwill come from a background in vertebrate systems, where the field has progressed most rapidly, and it is this group who should recognize its impact. It has become apparent that cytosine methylation is “cleared” at the time of fertilization, only to be fully reestablished by the time of implantation. Thus, active demethylation occurs, and complex patterns of methylation can be reproducibly established de novo. The importance of these effects is signaled by the discovery that mouse embryos carrying a homozygous mutation in the unique methyltransferase gene that lowers its level of expression to about 30% of wild type are not viable after the time of implantation (Li et al., Cell 69, 915-926, 1992). The inference is that an incompletely methylated genome cannot properly direct the complex repertoire of embryonic development, although one cannot exclude the possibility that methyltransferase has other essential functions. Two additional recent discoveries tighten the association of m5C with key biological processes. First, endogenous genes have been identified whose methylation patterns correlate with parental imprinting (pp. 481-482):
imprinted genes are only expressed when inherited from one particular parent. Since the patterns of methylation in various sequence elements differ between the mature sperm and the mature oocyte (pp. 343-350), it is tempting to attribute imprinting directly to methylation itself. Second, it is now clear that a predominance of inactivating mutations of the ~53 tumor suppressor gene in some human cancers are due to transitions resulting from deamination of m5C to T (Jones et al., Bioessays 74, 33-36, 1992; this volume, pp. 497-502). Indeed, methyltransferase itself may enzymatically deaminate cytosine under certain circumstances (Shen et al., Cell 77, 1073-1080, 1992). These examples serve to illustrate that we may not yet know why m5C is important in vertebrates but it is, and the field is poised to provide more answers about its functions. In this regard, this publication is timely and up-todate and provides a comprehensive background not available in other single sources. It covers the subject from methods to analyze methylation, to methytransferase, to methylation effects on DNA structure, to m5C-binding proteins and chromatin structure, to methylation patterns during development, and to methylation effects on expression of the best-studied gene and viral systems. The completeness is particularly valuable for those with limited knowledge of the field. For example, it is very helpful to have in one place separate presentations of data describing the different m5C-binding proteins that have been characterized to date. My discussion so far has centered on methylation in vertebrate systems because most readers are likely to work in that area. However, other systems are not neglected. In fact, reviews of prokaryotic, algal, fungal, and plant methylation preceding the vertebrate sections are important in their own right and provide a necessary perspective to the field. The particularly comprehensive chapter on m5C in plants will serve as an important reference source for plant biologists. The only gap in this volume concerns N6-methyldeoxyadenosine in eukaryotes. In ciliated protozoans, such as Tetrahymena thermophila, N6methyldeoxyadenosine is specific for macronuclear DNA and serves to distinguish specific molecular forms that are retained in that structure (e.g., Blackburn et al., Nucl. Acids Res. 11, 5131-5145, 1983; Capowski et al., Mol. Cell. Biol. 9,2598-2605,1989). There are also recent indications that NG-methyldeoxyadenosine has functional effects in plants. Given that the focus of this volume is on m5C, the omission of a chapter on NB-methyldeoxyadenosine is, perhaps, understandable. I got my copy of this book free. After reading it, I appreciate what a bargain that was. It belongs on my shelf and I would pay the price to put it there. It is so recommended. John C. Rogers Department of Biology Washington University St. Louis, Missouri 63130