Epigenetic regulation is fundamental to the existence of multicellular organisms, is essential for growth and development of eukaryotic organisms and is also responsible for the maintenance, and reversal of non genetic cellular memory that records developmental and environmental cues (Henikoff, 2008; Shilatifard, 2006; Suzuki and Bird, 2008; Bonasio et al., 2010). Epigenetic alterations during development can lead to cancer, neurological disorders, heart disease, and other degenerative conditions (Jiang et al., 2004). Epigenetic genome regulation involves enzyme-mediated chemical modifications of DNA and its associated chromatin proteins (Feng et al., 2010), such modifications include cytosine methylation, post-translational modifications of histone (tails and cores), incorporation of histone variants, the positioning of nucleosomes and the function of noncoding RNAs (Feng and Jacobsen; Feng et al., 2010; Henderson and Jacobsen, 2007; Law and Jacobsen, 2009). Paramutation
Paramutation is the epigenetic transfer of information from one allele (or homologous sequence) to another that establishes a state of gene expression that is heritable through mitosis and meiosis for generations. Paramutation has been reported between alleles of a gene, between two transgenes, or one transgene and one endogenous gene (Chandler and Stam, 2004). Paramutation was discovered in maize in the 1950s by Alexander Brink (Brink, 1956). The most thoroughly analyzed natural examples of paramutation involve four different loci, r1, b1, pl1 and p1 in maize (Brink, 1956; Chandler et al., 2000; Chandler and Stam, 2004; Coe, 1959; Hollick et al., 1995; Sidorenko and Peterson, 2001), which encode transcription factors that activate the biosynthesis of colored flavonoid pigments (Dooner et al., 1991; Goff et al., 1992). These pigments accumulate in most mature plant tissues and are not essential for plant survival (Dooner et al., 1991). One possible explanation for the discovery of paramutation at these loci is that the amount of pigment observed exquisitely reflects the expression levels of these regulatory genes such that even subtle (i.e. two fold) changes in expression are visually distinguishable (Hollick et al., 2000; Patterson et al., 1993). Paramutation-related processes have also been described in fungi and animals (Chandler, 2007; Chandler and Stam, 2004; Cuzin et al., 2008; Suter and Martin, 2009). The study of paramutation should shed light on fundamental mechanism for gene regulation (Suter and Martin,2009), potential roles of paramutation and consequences include that paramutation provides an adaptive mechanism in the absence of genetic variation through the transfer of favorable expression states to progeny, that paramutation could be a mechanism for establishing functional homozygosity in polyploids, and that it might function in inbreeding depression and hybrid vigor or inheritance associated with complex human diseases (Chandler, 2007; Suter and Martin, 2009). Independent of paramutation’s function or frequency, our understanding of its mechanisms should shed light on potentially novel mechanisms for transmitting epigenetic information across generations (Chandler, 2010). Paramutation at the b1 locus in maize Paramutation at the b1 locus in maize is the most stable and penetrant paramutation natural system described to date (Arteaga-Vazquez and Chandler, 2010). The b1 locus encodes a transcription factor required to activate the anthocyanin biosynthetic pathway, resulting in purple pigmentation of most mature plant tissues. The amount of transcription of b1 quantitatively correlates with the pigment levels in plants providing a powerful system for investigating paramutation (Patterson et al., 1993). When an allele’s expression is changed (i.e. sensitive to paramutation), it is referred to as paramutable. The allele that induces the change in expression is referred to as paramutagenic. Following paramutation, previously paramutable (sensitive alleles) are termed paramutant (or paramutated). Paramutated alleles are capable of inducing paramutation; they become paramutagenic. Most alleles do not participate in paramutation (they neither induce a change nor are they changed in the presence of a paramutagenic allele); these types of allele are referred to as neutral (Chandler, 2004). When the highly transcribed, darkly pigmented B-I allele is crossed with B’, which is lightly pigmented and has much lower transcription, paramutation always occurs: B-I is always changed into B’. This new B’ allele (designated as B’*) is as paramutagenic as the parental B’ allele. The key sequences required for b1 paramutation are seven direct tandem repeats of noncoding DNA located ~100 kb upstream of the b1 transcription start site (Stam et al., 2002a; Stam et al., 2002b). Each of the repeat units is 853 bp and both B-I and B’ carry seven tandem repeats, whereas neutral alleles have a single copy of the repeat unit (Stam et al., 2002a; Stam et al., 2002b). Recent results indicate that paramutation involves RNA mediated heritable chromatin changes and a number of genes implicated in RNA-based transcriptional silencing and chromatin modification pathways (Arteaga-Vazquez and Chandler, 2010). Genes required for paramutation
Several genes required for paramutation have been identified through forward genetic screens. The mediator of paramutation (mop) genes (Dorweiler et al., 2000; Sidorenko et al., 2009) and the required to maintain repression (rmr) genes (Erhard et al., 2009; Hollick and Chandler, 2001; Stonaker et al., 2009) have been isolated using the b1 and pl1 systems, respectively. All except one (rmr2) of the cloned genes show homology with proteins that mediate RNA-based transcriptional silencing (Arteaga-Vazquez and Chandler, 2010). In Arabidopsis, this pathway is referred to as RNA-directed DNA methylation (RdDM) and it involves the production of 24-nt short interfering RNAs (siRNAs) that are able to guide de novo cytosine methylation and histone modifications characteristic of heterochromatin, in the homologous genomic regions (Law and Jacobsen, 2010; Matzke et al., 2009) (Figure 2). In plants, the vast majority of cellular small RNAs correspond to 24-nt siRNAs derived from transposons that direct the establishment of heterochromatin at these repetitive regions (Matzke et al., 2009; Nobuta et al., 2008). mop1 encodes the maize ortholog of Arabidopsis RNA-dependent RNA polymerase 2 (RDR2) (Alleman et al., 2006; Nobuta et al., 2008), rmr1 encodes a SNF2-like chromatin remodeling factor related to Arabidopsis DRD1 and CLSY1 (Hale et al., 2007), rmr6 is an ortholog of the large subunit of Arabidopsis Pol IV (NRPD1) (Erhard et al., 2009); mop2 and rmr7 are paralogs of NRPD2/NRPE2, the shared second largest subunit of Pol IV and Pol V in Arabidopsis (Sidorenko et al., 2009; Stonaker et al., 2009). Pol-IV and Pol-V are Pol-II related enzyme complexes, limited to the plant kingdom, which are required for RNA-mediated transcriptional silencing of transposons and transgenes (Pikaard et al., 2008; Pikaard and Tucker, 2009). While it is clear that multiple genetic components are in common between paramutation in maize and RdDM in Arabidopsis, there are unique and distinct properties of paramutation that have yet to be demonstrated by RdDM. For example, the silent state established by RdDM is not heritable when separated from the locus driving the production of siRNAs, but most importantly, they are not paramutagenic, they cannot silence active alleles (Chan et al., 2006; Chandler, 2007; Henderson and Jacobsen, 2007; Matzke et al., 2009). Research at the epilab The existence of paramutation challenges traditional paradigms for how genes are regulated and inherited. Although the sequences required for paramutation have been identified for two loci (b1 and p1) and recent results demonstrate a role for RNA and the requirement of components of an RNA-based transcriptional silencing pathway (Arteaga-Vazquez and Chandler, 2010), many questions remain. How do homologous sequences communicate to establish distinct states of expression? Once established, how are the new expression states maintained through subsequent mitotic and meiotic divisions in the absence of DNA sequence changes? What is the heritable molecular mark or signal? (Chandler, 2007). At the epilab, we are addressing the following key questions that will shed light on the molecular mechanisms mediating transgenerational epigenetic inheritance and on fundamental aspects of developmental control of gene expression:1) When does the trans-comunication that establishes paramutation occur? 2) What is the developmental role of genes required for paramutation during gamete formation and embryogenesis? 3) What is the widespread influence of paramutation in plants and other multicellular eukaryotes? References Shilatifard, A. (2006). Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression. 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