Transcriptional repression of euchromatic genes by Drosophila heterochromatin protein 1 and histone modifiers

Abstract

In Drosophila, heterochromatin protein 1 (HP1) suppresses the expression of euchromatic genes that are artificially translocated adjacent to heterochromatin by expanding heterochromatin structure into neighboring euchromatin. The purpose of this study was to determine whether HP1 functions as a transcriptional repressor in the absence of chromosome rearrangements. Here, we show that Drosophila HP1 normally represses the expression of four euchromatic genes in a dosage-dependent manner. Three genes regulated by HP1 map to cytological region 31 of chromosome 2, which is immunostained by anti-HP1 antibodies in the salivary gland. The repressive effect of HP1 is decreased by mutation in Su(var)3-9, whose mammalian orthologue encodes a histone H3 methyltransferase and mutation in Su(var)2-1, which is correlated with histone H4 deacetylation. These data provide genetic evidence that an HP1-family protein represses the expression of euchromatic genes in a metazoan, and that histone modifiers cooperate with HP1 in euchromatic gene repression.H eterochromatin protein 1 (HP1) first was identified as a component of heterochromatin in Drosophila polytene chromosomes (1). Subsequently, it was shown to mediate variegated silencing of euchromatic genes that are placed abnormally next to constitutive heterochromatin, a phenomenon known as position-effect variegation (PEV; refs. 2-4). In contrast to its role in suppressing genes that are localized abnormally on chromosomes, the only documented role of HP1 in normal gene regulation is in the activation of two Drosophila heterochromatic genes, light and rolled (5).HP1-family proteins bind to histones and DNA (6-9). Lys-9 of histone H3 is methylated by the modifier proteins SUV39H1 and Suv39H1, the human and murine orthologues of the Drosophila Su(var)3-9 gene product, respectively (10, 11). Histone H3 methylation is thought to promote transcriptional silencing by creating a binding site for HP1-family proteins to form heterochromatic subdomains (6-8). Histone deacetylation also is thought to promote silencing. Mutations in the Drosophila histone deacetylase (HDAC) 1 suppress PEV, indicating that HDAC1 normally promotes silencing (12). Similarly, Su(var)2-1 mutations suppress PEV silencing and cause hyperacetylation of histones (13).Although HP1 is involved in heterochromatin structure and position-effect silencing, there are no examples of normal transcriptional repression of genes by HP1. Among HP1-family proteins, only Swi6p in fission yeast has been shown to be involved in normal gene repression, silencing the mating type cassettes (14, 15). Here, we describe a previously unreported role for HP1 in the repression of euchromatic genes in Drosophila. We have identified genes residing in the euchromatin of chromosome 2 that are repressed normally by HP1 and other heterochromatin-associated factors. In contrast to previous examples of euchromatic gene silencing by heterochromatin, these HP1-repressed genes are located well away from constitutive heterochromatin. The genes show a gr...

Does heterochromatin protein 1 always follow code?

“…Interestingly, one of the genes misregulated in the HP1 homozygous mutant maps to cytological region 31, a chromosome division that stains intensely with antibodies to HP1 (7). Two additional randomly selected genes within region 31 show up-regulation in HP1 homozygous mutants (59). For all four candidate HP1 target genes, mutations in additional modifiers of PEV, including Su(var)3-9, cause increases in gene expression.…”

“…HP1 associates with origin recognition complex (ORC) proteins (58,59). This presents an intriguing parallel to the situation in Saccharomyces cerevisiae where ORC proteins associate with silent information regulator (SIR) proteins to generate silent chromatin (60,61).…”

“…As a second approach to determine the effects of HP1 on gene expression at locations other than centric heterochromatin, investigators have identified potential target genes by their response to HP1 dosage. Representational difference analysis identified two genes that are up-regulated in homozygous HP1 mutant larvae (59). Interestingly, one of the genes misregulated in the HP1 homozygous mutant maps to cytological region 31, a chromosome division that stains intensely with antibodies to HP1 (7).…”

Isoform-specific interaction of HP1 with human TAF II 130

“…38 and 39); however, the precise mechanisms of HP1 repression are not well understood. HP1 has been shown to play a role not only in heterochromatic silencing but also in normal repression of genes in euchromatin (51). In mammalian cells and Schizosaccharomyces pombe, it has been reported that HP1͞Swi6 chromodomain binds to histone H3 methylated by the methyltransferase SUV39H1͞Clr4 at Lys-9 (52-54).…”

Mutations in Su(var)205 and Su(var)3-7 Suppress P-Element-Dependent Silencing in Drosophila melanogaster

“…SU(VAR)3-9 (Hwang et al 2001) ] strongly suppress PDS. Therefore these zinc fingers are necessary for SU(VAR) 3-7-dependent silencing in vivo.…”