Heterochromatin protein 1 (HP1) functions in gene silencing, transcriptional regulation, and chromatin remodeling. Drosophila HP1 enhances position effect variegation and has also been shown to repress transcription of some euchromatic genes and activate some heterochromatic ones. The purpose of this study was to determine if human orthologs of Drosophila HP1 differentially regulate transcription by identifying genes that are targets for regulation by HP1 family proteins in human cells. Using a gene expression array, we identify several genes regulated by overexpression of the three human HP1 family proteins HP1(Hsalpha) HP1(Hsbeta) and HP1(Hsgamma). We show further that overexpressed HP1(Hsalpha) and HP1(Hsbeta) repress the transcription of four human genes while overexpressed HP1(Hsgamma) enhances transcription of the same genes. These results show that different human HP1 family proteins can potentially repress or activate the same genes. (C) 2002 Elsevier Science (USA). All rights reserved.