Figure 1

Summary of relationship between epitype and DNA sequence. A. Theoretical ground state for a chromatin structure comprised of naked DNA bound to two nucleosomes and an unbound upstream DNA region. Every 10 bp the approximately 2 bp of inward facing surface of the DNA helix has the potential to contact and bind nucleosomal histones (for example, yellow ovals numbered 1 to 23 for region surrounding one nucleosome, see B). Each nucleosome has the potential to bind 14 such 2 bp regions. B. One 10 bp region of the DNA helix with the consensus ((Y)RRRRRYYYYY(R) provides a bend for optimal nucleosome binding. Nucleotides that provide strong or weak nucleosome binding are indicated (S = strong binding to G or C nucleotides, W = weak binding to A or T nucleotides, R = purine, Y = pyrimidine, IN identifies the surface facing the nucleosome, and OUT the surface facing away from the nucleosome). The strength of nucleosome binding and positioning to 147 bp stretches of DNA appears to be determined by the sum of affinities for 14 small sequences (yellow ovals, same as in A). C. Double stranded (ds) RNAs (for example, siRNA, piRNA, miRNA) program cytosine methylation for transgenerational inheritance and somatic inheritance in different tissues, while various enzymes remove 5MeC. D. Mutations such as single nucleotide polymorphisms (SNPs, red dot) and inserted retrotransposons (RT, red line) may alter nucleosome binding and the stochastic movement of nucleosomes. E. Histone variant exchange (HVE) by a subset of chromatin remodeling complexes (for example, SWR1) replaces common core histones (for example, H2A) with specialized protein sequence variants (for example, H2AZ, H2AX). F. A variety of histone post-translational modifications (PTMs) of primarily lysine and arginine residues at the N- and C-termini of core histones produce a diverse “histone code” for different nucleosomes. G. A large number of chromatin remodeling machines (for example, SWI/SNF, INO80) control nucleosome positioning, often moving nucleosomes in approximately 10 bp increments. Not shown is that the individual epitypes interact with each other to produce complex epitypes. For example, a subset of individuals may contain in their genome a retrotransposons that is targeted by small RNAs, which cause the hypermethylation or hypomethylation of adjacent sequences and alters gene expression (that is, the interaction of C and D).