Conformation Regulation of the X Chromosome Inactivation Center: A Model

Abstract

X-Chromosome Inactivation (XCI) is the process whereby one, randomly chosen X becomes transcriptionally silenced in female cells. XCI is governed by the Xic, a locus on the X encompassing an array of genes which interact with each other and with key molecular factors. The mechanism, though, establishing the fate of the X's, and the corresponding alternative modifications of the Xic architecture, is still mysterious. In this study, by use of computer simulations, we explore the scenario where chromatin conformations emerge from its interaction with diffusing molecular factors. Our aim is to understand the physical mechanisms whereby stable, non-random conformations are established on the Xic's, how complex architectural changes are reliably regulated, and how they lead to opposite structures on the two alleles. In particular, comparison against current experimental data indicates that a few key cis-regulatory regions orchestrate the organization of the Xic, and that two major molecular regulators are involved.

Author Summary

In mammal female cells X-Chromosome Inactivation (XCI) is the vital process whereby one X, randomly chosen, is silenced to compensate dosage of X products with respect to males. XCI is governed by a region on the X, the X Inactivation Centre ( Xic), which undergoes a sequence of conformational modifications during the process. The two Xic are exposed, though, to the same environment, and it is obscure how they attain different architectures. By use of computer simulations of a molecular model, here we individuate general physical mechanisms whereby random Brownian molecules can assemble chromatin stable architectures, reliably regulate conformational changes, and establish opposite transformations on identical alleles. In the case-study of the murine Xic, our analysis highlights the existence of a few key regulatory regions and molecular factors. It also predicts, e.g., the effects of genetic modifications in the locus, which are compared with current deletion/insertion experiments. The physical mechanisms we describe are rooted in thermodynamics and could be relevant well beyond XCI.