self-assembly and dna binding of the blocking factor in x chromosome inactivation自组装和dna结合x染色体失活的阻碍因素.pdfVIP

Self-Assembly and DNA Binding of the Blocking Factor in X Chromosome Inactivation Mario Nicodemi1,2*, Antonella Prisco3 1 Complexity Science and Department of Physics, University of Warwick, Warwick, United Kingdom, 2 Istituto Nazionale di Fisica Nucleare (INFN), Naples, Italy, 3 Institute of Genetics and Biophysics (IGB) ‘‘A. Buzzati Traverso’’ (ABT), CNR, Naples, Italy 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 ‘‘