How do DNA mismatches effect genetic vs. epigenetic inheritance patterns? (I had
ID: 16895 • Letter: H
Question
How do DNA mismatches effect genetic vs. epigenetic inheritance patterns? (I had to answer first the difference between genetic and epigenetic inheritance).Note: this response should be in relation to mismatch-mediated error prone repair at the immunoglobulin genes discussion (in regards to the generation of effective antibodies which depends upon somatic hypermutation (SHM) and class-switch recombination (CSR) of antibody genes by activation induced cytidine deaminase (AID) and the subesequent recruitment of error prone base excision and mismatch repair).
Explanation / Answer
The character of a cell is defined by its constituent proteins, which are the result of specific patterns of gene expression. Crucial determinants of gene expression patterns are DNA-binding transcription factors that choose genes for transcriptional activation or repression by recognizing the sequence of DNA bases in their promoter regions. Interaction of these factors with their cognate sequences triggers a chain of events, often involving changes in the structure of chromatin, that leads to the assembly of an active transcription complex (e.g., Cosma et al. 1999). But the types of transcription factors present in a cell are not alone sufficient to define its spectrum of gene activity, as the transcriptional potential of a genome can become restricted in a stable manner during development. The constraints imposed by developmental history probably account for the very low efficiency of cloning animals from the nuclei of differentiated cells (Rideout et al. 2001; Wakayama and Yanagimachi 2001). A “transcription factors only” model would predict that the gene expression pattern of a differentiated nucleus would be completely reversible upon exposure to a new spectrum of factors. Although many aspects of expression can be reprogrammed in this way (Gurdon 1999), some marks of differentiation are evidently so stable that immersion in an alien cytoplasm cannot erase the memory. The genomic sequence of a differentiated cell is thought to be identical in most cases to that of the zygote from which it is descended (mammalian B and T cells being an obvious exception). This means that the marks of developmental history are unlikely to be caused by widespread somatic mutation. Processes less irrevocable than mutation fall under the umbrella term “epigenetic” mechanisms. A current definition of epigenetics is: “The study of mitotically and/or meiotically heritable changes in gene function that cannot be explained by changes in DNA sequence” (Russo et al. 1996). There are two epigenetic systems that affect animal development and fulfill the criterion of heritability: DNA methylation and the Polycomb-trithorax group (Pc-G/trx) protein complexes. (Histone modification has some attributes of an epigenetic process, but the issue of heritability has yet to be resolved.) This review concerns DNA methylation, focusing on the generation, inheritance, and biological significance of genomic methylation patterns in the development of mammals. Data will be discussed favoring the notion that DNA methylation may only affect genes that are already silenced by other mechanisms in the embryo. Embryonic transcription, on the other hand, may cause the exclusion of the DNA methylation machinery. The heritability of methylation states and the secondary nature of the decision to invite or exclude methylation support the idea that DNA methylation is adapted for a specific cellular memory function in development. Indeed, the possibility will be discussed that DNA methylation and Pc-G/trx may represent alternative systems of epigenetic memory that have been interchanged over evolutionary time. Animal DNA methylation has been the subject of several recent reviews (Bird and Wolffe 1999; Bestor 2000; Hsieh 2000; Costello and Plass 2001; Jones and Takai 2001). For recent reviews of plant and fungal DNA methylation, see Finnegan et al. (2000), Martienssen and Colot (2001), and Matzke et al. (2001). Next Section Variable patterns of DNA methylation in?animals A prerequisite for understanding the function of DNA methylation is knowledge of its distribution in the genome. In animals, the spectrum of methylation levels and patterns is very broad. At the low extreme is the nematode worm Caenorhabditis elegans, whose genome lacks detectable m5C and does not encode a conventional DNA methyltransferase. Another invertebrate, the insect Drosophila melanogaster, long thought to be devoid of methylation, has a DNA methyltransferase-like gene (Hung et al. 1999; Tweedie et al. 1999) and is reported to contain very low m5C levels (Gowher et al. 2000; Lyko et al. 2000), although mostly in the CpT dinucleotide rather than in CpG, which is the major target for methylation in animals. Most other invertebrate genomes have moderately high levels of methyl-CpG concentrated in large domains of methylated DNA separated by equivalent domains of unmethylated DNA (Bird et al. 1979; Tweedie et al. 1997). This mosaic methylation pattern has been confirmed at higher resolution in the sea squirt, Ciona intestinalis (Simmen et al. 1999). At the opposite extreme from C. elegans are the vertebrate genomes, which have the highest levels of m5C found in the animal kingdom. Vertebrate methylation is dispersed over much of the genome, a pattern referred to as global methylation. The variety of animal DNA methylation patterns highlights the possibility that different distributions reflect different functions for the DNA methylation system (Colot and Rossignol 1999). Previous Section Next Section Mammalian DNA methylation patterns vary in time and?space In human somatic cells, m5C accounts for ~1% of total DNA bases and therefore affects 70%–80% of all CpG dinucleotides in the genome (Ehrlich 1982). This average pattern conceals intriguing temporal and spatial variation. During a discrete phase of early mouse development, methylation levels in the mouse decline sharply to ~30% of the typical somatic level (Monk et al. 1987; Kafri et al. 1992). De novo methylation restores normal levels by the time of implantation. A much more limited drop in methylation occurs in the frog Xenopus laevis (Stancheva and Meehan 2000), and no drop is seen in the zebrafish, Danio rerio (MacLeod et al. 1999). Even within vertebrates, therefore, interspecies variation is seen that could reflect differences in the precise role played by methylation in these organisms. For mice and probably other mammals, however, the cycle of early embryonic demethylation followed by de novo methylation is critical in determining somatic DNA methylation patterns. A genome-wide reduction in methylation is also seen in primordial germ cells (Tada et al. 1997; Reik et al. 2001) during the proliferative oogonial and spermatogonial stages. The most striking feature of vertebrate DNA methylation patterns is the presence of CpG islands, that is, unmethylated GC-rich regions that possess high relative densities of CpG and are positioned at the 5' ends of many human genes (for review, see Bird 1987). Computational analysis of the human genome sequence predicts 29,000 CpG islands (Lander et al. 2001; Venter et al. 2001). Earlier studies estimated that ~60% of human genes are associated with CpG islands, of which the great majority are unmethylated at all stages of development and in all tissue types (Antequera and Bird 1993). Because many CpG islands are located at genes that have a tissue-restricted expression pattern, it follows that CpG islands can remain methylation-free even when their associated gene is silent. For example, the tissue-specifically expressed human a-globin (Bird et al. 1987) and a 2(1) collagen (McKeon et al. 1982) genes have CpG islands that remain unmethylated in all tested tissues, regardless of expression. A small but significant proportion of all CpG islands become methylated during development, and when this happens the associated promoter is stably silent. Developmentally programmed CpG-island methylation of this kind is involved in genomic imprinting and X chromosome inactivation (see below). The de novo methylation events occur in germ cells or the early embryo (Jaenisch et al. 1982), suggesting that de novo methylation is particularly active at these stages. There is evidence, however, that de novo methylation can also occur in adult somatic cells. A significant fraction of all human CpG islands are prone to progressive methylation in certain tissues during aging (for review, see Issa 2000), or in abnormal cells such as cancers (for review, see Baylin and Herman 2000) and permanent cell lines (Harris 1982; Antequera et al. 1990; Jones et al. 1990). The rate of accumulation of methylated CpGs in somatic cells appears to be very slow. For example, de novo methylation of a provirus in murine erythroleukemia cells took many weeks to complete (Lorincz et al. 2000). Similarly, the recovery of global DNA methylation levels following chronic treatment of mouse cells with the DNA methylation inhibitor 5-azacytidine required months (Flatau et al. 1984). How do patterns of methylated and unmethylated mammalian DNA arise in development and how are they maintained? Why are CpG islands usually, but not always, methylation-free? What causes methylation of bulk non-CpG-island DNA? These burning questions cannot be answered definitively at present, but there are distinct hypotheses that have been addressed experimentally. The available data will be conveniently considered in three parts: (1) mechanisms for maintaining DNA methylation patterns; (2) mechanisms and consequences of methylation gain; and (3) mechanisms and consequences of methylation loss.
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