Abstract
Eukaryotic chromosomes terminate in telomeres, complex nucleoprotein structures that are required for chromosome integrity that are implicated in cellular senescence and cancer. The chromatin at the telomere is unique with characteristics of both heterochromatin and euchromatin. The end of the chromosome is capped by a structure that protects the end and is required for maintaining proper chromosome length. Immediately proximal to the cap are the telomere associated satellite-like (TAS) sequences. Genes inserted into the TAS sequences are silenced indicating the chromatin environment is incompatible with transcription. This silencing phenomenon is called telomeric position effect (TPE). Two other silencing mechanisms have been identified in eukaryotes, suppressors position effect variegation [Su(var)s, greater than 30 members] and Polycomb group proteins (PcG, approximately 15 members). We tested a large number of each group for their ability to suppress TPE [Su(TPE)]. Our results showed that only three Su(var)s and only one PcG member are involved in TPE, suggesting silencing in the TAS sequences occurs via a novel silencing mechanism. Since, prior to this study, only five genes have been identified that are Su(TPE)s, we conducted a candidate screen for Su(TPE) in Drosophila by testing point mutations in, and deficiencies for, proteins involved in chromatin metabolism. Screening with point mutations identified seven new Su(TPE)s and the deficiencies identified 19 regions of the Drosophila genome that harbor suppressor mutations. Chromatin immunoprecipitation experiments on a subset of the new Su(TPE)s confirm they act directly on the gene inserted into the telomere. Since the Su(TPE)s do not overlap significantly with either PcGs or Su(var)s, and the candidates were selected because they are involved generally in chromatin metabolism and act at a wide variety of sites within the genome, we propose that the Su(TPE) represent a third, widely used, silencing mechanism in the eukaryotic genome.
Highlights
The proper development and health of an organism are the result of a complex interplay between regulatory systems that activate genes whose functions are necessary, and those that repress the activity of genes whose functions are not required
It is important to note that the phenotype associated with 39C-5 is due to the repressive effects of the telomere (TPE), since the same construct inserted into euchromatin of the X chromosome, in the 39C-X strain, gives fully pigmented, red eyes
Of a minimum of 15 Su(var) loci examined, and possibly as high as 30, only three of the Su(var) mutations, or 10 to 20%, suppressed telomeric position effect (TPE). This suggests that the mechanisms underlying position effect variegation (PEV) and TPE differ substantially
Summary
The proper development and health of an organism are the result of a complex interplay between regulatory systems that activate genes whose functions are necessary, and those that repress the activity of genes whose functions are not required. The mechanism of action of the majority of PcG proteins remains unknown Some, such as E(z), are in involved in complexes that modify nucleosome structure through methylation of H3K27 [7,8,9,10,11]. For the majority of the PcG proteins, the only clues to their functions come from experiments that show they bind to the promoters and to regulatory regions upstream of and within target genes. It is widely believed they create or promote an alteration in chromatin structure that represses transcription, but their mechanism(s) of action remain enigmatic [1,2,3,4]
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