Model for nucleosome modification circuits, using a code with two histone modifications.

<p>(A) A simple modification scheme previously shown to be capable of giving heritable bistability <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002643#pcbi.1002643-Micheelsen1" target="_blank">[24]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002643#pcbi.1002643-Dodd2" target="_blank">[25]</a> in which one residue per nucleosome is either unmodified (0) or modified (1), generating two nucleosome types, each associated with a distinct epigenetic regulatory state (E1 or E2). The grey box indicates the nucleosome type (R) that is added after DNA replication, which causes roughly half of the nucleosomes in the system to be converted to the R type. Interconversion reactions (red arrows) may occur at a rate that is unaffected by nearby nucleosomes (dashed red arrows) or are stimulated by enzymes recruited by other nucleosomes (green arrows). The green double-tailed arrow indicates direct cooperativity due to recruitment by two nucleosomes. (B) A three nucleosome-type scheme also shown to give heritable bistability <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002643#pcbi.1002643-Dodd1" target="_blank">[11]</a>, <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1002643#pcbi.1002643-Sneppen1" target="_blank">[21]</a>, in which a single residue per nucleosome can exist in three modification states (e.g. H3K9ac, H3K9 and H3K9me). (C) Extended scheme analyzed here in which each nucleosome can be modified (1) or not (0) at two different histone positions, making a total of 4 nucleosome types (00, 10, 01, 11; e.g. H3K4K9, H3K4meK9, H3K4K9me, H3K4meK9me). [Note that our model effectively only considers the modification combinations for each half-nucleosome (one copy of each histone protein), whereas two binary modifications on each half nucleosome give 10 different full-nucleosome types (00/00, 00/01, 00/10, 00/11, 01/01, 01/10, 01/11, 10/10, 10/11, 11/11)]. Enzymatic transitions between types are by addition or removal of one modification. Each of the patterns of recruitment-reaction connections are defined by a specific circuit code that lists the recruiting nucleosome (0, 1, 2, 3) for each of the eight reactions; non-recruited ‘noise’ transitions are denoted ‘x’. We term the specific circuit shown in (C) the “classical” motif due to its similarity with the previously studied three nucleosome-type motif shown in (B). (D) Time course displaying strong bistability for the circuit in (C), showing the numbers of E1 and E2 nucleosomes in a 30 nucleosome system (with noise level ).