The invention is directed to compositions and methods for RNA-mediated gene regulation, e.g., transcription regulation, e.g., by transcriptional silencing of genes. In one aspect, the invention provides methods using siRNAs directed at a transcription regulator, e.g., a promoter or enhance sequence, of a gene target molecule. In one aspect, this results in in vivo DNA methylation and/or modification of associated chromatin (e.g., histone proteins) accompanied by and/or partial or complete transcription gene silencing in a cell, such as a mammalian cell, e.g., a human cell.