Self-assembly and DNA binding of the blocking factor in x chromosome inactivation

PLoS Comput Biol. 2007 Nov;3(11):e210. doi: 10.1371/journal.pcbi.0030210. Epub 2007 Sep 18.

Abstract

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."

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chromosomes, Human, X / genetics*
  • Computer Simulation
  • DNA / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Humans
  • Models, Genetic*
  • Models, Statistical
  • Protein Binding
  • Sequence Analysis, DNA / methods*
  • X Chromosome Inactivation / genetics*

Substances

  • DNA-Binding Proteins
  • DNA