X inactivation, differentiation, and DNA methylation

Abstract

A model based on DNA methylation is proposed to explain the initiation and maintenance of mammalian X inactivation and certain aspects of other permanent events in eukaryotic cell differentiation. A key feature of the model is the proposal of sequence-specific DNA methylases that methylate unmethylated sites with great difficulty but easily methylate half-methylated sites. Although such enzymes have not yet been detected in eukaryotes, they are known in bacteria. An argument is presented, based on recent data on DNA-binding proteins, that DNA methylation should affect the binding of regulatory proteins. In support of the model, short reviews are included covering both mammalian X inactivation and bacterial restriction and modification enzymes.

In this paper I attempt to explain mammalian X inactivation on the bases of DNA methylation and the properties of bacterial DNA methylases. Since most readers familiar with bacterial methylases may not be familiar with the X inactivation phenomenon, and vice versa, it was thought necessary to review briefly both areas before presenting new models.

The X inactivation phenomenon
Female mammals have two X chromosomes, whereas males have only one, creating a potential gene-dosage differential. In fact, however, this differential does not exist because a mechanism has evolved to maintain gene dosage effectively constant in both sexes. This mechanism, called X inactivation, results in one, and only one, active X chromosome per diploid autosomal set of chromosomes. Any additional X chromosomes are genetically inactive, heteropyknotic, and late replicating. The condensed, inactive X chromosome forms the sex chromatin, or Barr body...