DNA methylation patterns and epigenetic memory.

By A. Bird. 2002

7,204 citations recorded by the source corpus.

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).

Subfields: Genetics, Molecular Biology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. Hao Wu
2. Yi Zhang
3. Manel Esteller
4. Peter A. Jones
5. A. Bird
6. Wolf Reik
7. Michael Joseph Meaney
8. S. Baylin

In Molecular Biology

1. Hao Wu
2. Manel Esteller
3. Peter A. Jones
4. Yi Zhang
5. A. Bird
6. Heng Li
7. Peter W. Laird
8. S. Baylin

Citations in the corpus

• Impact of cytosine methylation on DNA binding specificities of human transcription factors (2017, background): “In addition, methylation patterns vary between cell types (3), and the changes correlate with gene expression.”
• The mammalian epigenome. (2007, background): “By regulating chromatin structure and DNA accessibility, these chemical changes influence how the genome is made manifest across a diverse array of developmental stages, tissue types, and disease states (Bird, 2002; Goll and Bestor, 2005; Margueron et al., 2005).”
• edgeR v4: powerful differential analysis of sequencing data with expanded functionality and improved support for small counts and larger datasets (2024, positive): “Given the fact that unmethylated CpGs are often enriched in gene promoters [, 13 , 68–70 ], a gene oriented differential methylation analysis can be conducted by aggregating the methylated and un-methylated CpG counts in gene promoter regions [ 13 ].”
• A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “2 ), affecting some 5–10% of the thousands of promoter CpG islands that never normally contain DNA methylation from embryonic development onward”
• Mapping and elucidating the function of modified bases in DNA (2017, background): “4 inactivation, genomic imprinting [G] and transposon silencing [G].(11,12,13,14)”
• Epigenetics in cancer. (2010, background): “inactivation and imprinted genes are classic examples of such naturally occurring CpG island methylation during development [15].”
• Epigenomic Analysis of Multi-lineage Differentiation of Human Embryonic Stem Cells (2013, positive): “DNA methylation at promoters has been shown to silence gene expression and thus has been proposed to be necessary for lineage-specific expression of developmental regulatory genes, genomic imprinting, and X chromosome inactivation (Bird, 2002).”
• Genomic imprinting: the emergence of an epigenetic paradigm (2011, background): “In mammalian cells, DNA methylation modifies predominantly CpG dinucleotides and is associated with a transcriptionally repressed stat”
• DNA hypomethylation and human diseases. (2007, background): “In the healthy genome, most CpG islands are unmethylated, and associated genes expressed [34] while the lone CpGs found dispersed throughout the rest of the DNA are mostly methylated [38].”
• Reduced representation bisulfite sequencing for comparative high-resolution DNA methylation analysis (2005, background): “( 42 )]. For example, >80% of the loci in the HEP survey of the MHC were either hypermethylated or hypomethylated (29).”
• A Six Months Exercise Intervention Influences the Genome-wide DNA Methylation Pattern in Human Adipose Tissue (2013, positive): “This supports the view that the human methylome can dynamically respond to changes in the environment [14,15].”
• The nucleosome: from genomic organization to genomic regulation. (2004, neutral): “The SANT domain, al-see Bird, 2002).”
• Epigenetic reprogramming in mammals. (2005, background): “It is thought that this is substantially regulated by epigenetic modifications such as DNA methylation, histone tail modifications and non-histone proteins that bind to chromatin (1,2).”