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Epigenetics – A Science of Heritable Biological Adaptation

This annual review issue is dedicated to “Epigenetics” an emerging but fast growing field in the postgenomic era involving nonMendelian heritable changes in gene expression that are not mediated by alterations in Watson-Crick basepairing of the DNA sequence (1,2). Conrad Waddington (1905–1975) coined the term “epigenetics” and defined it as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being” (1,2). Both Darwin and Lamarck, the founders of evolutionary theory, predicted that “evolution may favor the development of self-guiding mechanisms, maximizing variability where and when it is most likely to yield positive changes while minimizing phenotypic variability when and where it is not needed” (1,2), supporting the general idea of nonrandom evolution. Epigenetic regulation mediates adaptation to the environment by the genome lending plasticity that translates into the presenting phenotype, particularly under “mismatched” environmental conditions (3). Most investigations focus on demonstrating chemical modifications of the DNA sequence and/or the nuclear histone proteins that in turn alter the configuration of chromatin affecting its packaging and accessibility within the nucleus. The state of chromatin is critically important for the transcription of genes. Thus, heterochromatin signifies tightly wound chromatin impeding access of specific DNA sequences (ciselements) by nuclear trans-activating proteins, a process that inhibits gene transcription. On the other hand, euchromatin is an active state, in which the loosely wound chromatin allows binding of the promoter region of genes by activating proteins resulting in active transcription. This simple concept, while serving as the ultimate process, is complicated by nuclear transport via the nuclear membrane pore or retention of critically important proteins, the complex nuclear arrangement of chromatin and proteins in a network creating loops and higher order structures, and recruitment of various enzymes and proteins to transcription initiation complexes, that are vital for either activating or repressing transcription (4,5), along with the newly evolving role for noncoding RNAs (6,7). The organization of chromatin in the nucleus allows the close proximity of the 5=and 3=ends of chromatin setting the stage for factors that mediate mRNA processing at the 3=-end to be involved in transcription at the 5=-end. Further, the approximation of chromosomes lends to the process of nonrandom translocation that determines a particular cellular phenotype (4,5). This self-organization of the nucleus is thought to be responsible for the formation of nucleoli either in the presence or absence of a scaffolding network consisting of lamin and/or actin filaments (4,5). Cytosine methylation of CpG dinucleotide clusters at the carbon 5 position found in close proximity to critically important cis-elements within the promoter can silence a gene. De novo and maintenance DNA methyl transferase enzyme isoforms (Dnmt1, 3a, 3b) responsible for methylating DNA and repressor methyl-binding domain (MBD 1, 2, 3) proteins or methyl CpG binding proteins (MeCP 1, 2) are necessary for mediating and/or modifying this reaction (8). Methylated DNA in turn attracts chromodomain binding proteins (heterochromatin protein, HP1) that maintain the heterochromatin state. What lends to further complexity is the long range chromatin interactions that occur which may not be evident at first pass when examining the promoter region of a gene where a concentration of unmethylated CpG islands tend to cluster (9). Usually CpGs in a GC rich region with excluded Alu repeats within a promoter are unmethylated and conserved across species while CpGs within or in close proximity to transposans or repeats are methylated (9). The mammalian one carbon metabolism provides the methyl groups for all biologic methylation reactions that in turn is dependent on methyl donors (methionine and choline) and co-factors (folic acid, vitamin B12, pyridoxal phosphate). Examples of the genome that carry methylated CpG regions as seen in the centromere, in the imprinting control regions (ICRs) which are characterized by differentially methylated regions (DMRs) are called “methylation marks” (4,8). These imprints resulting in gene silencing are seen with transposans, X-chromosome inactivation and parenterally imprinted genes causing mono-allelic gene expression (IGF 2, IGF2 receptor genes, Peg) (4). The genome of the immature primordial germ cells of the developing embryo (zygote and blastomeres) undergoes extensive demethylation allowing for totipotency while erasing methylation marks thereby repressing the somatic program (10). Subsequent re-establishment of appropriate sexdependent patterns of cytosine methylation during gametogenesis sets the stage for pluripotency that is maintained through embryonic development during many rounds of rapid cellular proliferation (mitosis) until final maturation of cell differentiation. The re-establishment of methylation imprints occurs Correspondence: Sherin U. Devaskar, M.D., David Geffen School of Medicine at UCLA, Department of Pediatrics, Division of Neonatology and Developmental Biology, 10833 Le Conte Avenue, Room B2-375 MDCC, Los Angeles, CA 90095, Phone: (310) 825-9436, Fax: (310) 267-0154; e-mail: SDevaskar@mednet.ucla.edu Statement of Financial Support: The authors are supported by grants from NICHD HD-25024, -33997, -41230 [S.U.D.] and -46979 [S.U.D., S.R.].