Self-assembly and DNA binding of the blocking factor in x chromosome inactivation.
X chromosome inactivation (XCI) is the phenomenon occurring in female mammals whereby dosage compensation of X-linked genes is obtained by transcriptional silencing of one of their two X chromosomes, randomly chosen during early embryo development. The earliest steps of random X-inactivation, involving counting of the X chromosomes and choice of the active and inactive X, are still not understood. To explain "counting and choice," the longstanding hypothesis is that a molecular complex, a "blocking factor" (BF), exists. The BF is present in a single copy and can randomly bind to just one X per cell which is protected from inactivation, as the second X is inactivated by default. In such a picture, the missing crucial step is to explain how the molecular complex is self-assembled, why only one is formed, and how it binds only one X. We answer these questions within the framework of a schematic Statistical Physics model, investigated by Monte Carlo computer simulations. We show that a single complex is assembled as a result of a thermodynamic process relying on a phase transition occurring in the system which spontaneously breaks the symmetry between the X's. We discuss, then, the BF interaction with X chromosomes. The thermodynamics of the mechanism that directs the two chromosomes to opposite fates could be, thus, clarified. The insights on the self-assembling and X binding properties of the BF are used to derive a quantitative scenario of biological implications describing current experimental evidences on "counting and choice."
Nicodemi
Mario
M
Complexity Science and Department of Physics, University of Warwick, Warwick, United Kingdom. Mario.Nicodemi@na.infn.it
Prisco
Antonella
A
D001665:Binding Sites; D041321:Chromosomes, Human, X / Q000235:genetics*; D003198:Computer Simulation; D004247:DNA / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008957:Models, Genetic; D015233:Models, Statistical; D011485:Protein Binding; D017422:Sequence Analysis, DNA / Q000379:methods*; D049951:X Chromosome Inactivation / Q000235:genetics*
D004268:DNA-Binding Proteins; D004247:DNA