Abstract: Methods of regulating the formation of heterochromatin at a target locus within the genome of a cell and methods of regulating the modification of a histone protein assumed on the DNA of a target locus within the genome of a cell are provided. In particular, the invention provides methods to regulate the structure of the genome of a cell, where the structure is regulated by modulating heterochromatin formation, heterochromatin architecture, histone methylation, and/or DNA methylation, by exposing the cell to an RNAi probe complementary to a target locus so as to activate the RNAi machinery to modify the genomic structure of the target locus and adjacent segments of the genome.