Heterochromatin protein 1 modifies mammalian PEV in a dose- and chromosomal-context- dependent manner

Abstract

Locus control regions (LCRs) are gene regulatory elements in mammals that can overcome the highly repressive effects normally associated with heterochromatic transgene locations (for example the centromere) in mice. Deletion of essential LCR sequences renders the cognate gene susceptible to this form of repression, so a proportion of the cells from transgenic mice that would normally express the transgene are silenced-a phenomenon known as position effect variegation (PEV). We show here that PEV can also occur when the transgene is non-centromeric and that the extent of variegation can be developmentally regulated. Furthermore, by overexpressing a mammalian homologue (M31) of Drosophila melanogaster heterochromatin protein 1 (HP1; refs 7,8) in transgenic mouse lines that exhibit PEV, it is possible to modify the proportion of cells that silence the transgene in a dose-dependent manner. Thus, we show M31 overexpression to have two contrasting effects which are dependent on chromosomal context: (i) it enhanced PEV in those lines with centromeric or pericentromeric transgene locations; and (ii) it suppressed PEV when the transgene was non-centromeric. Our results indicate that components or modifiers of heterochromatin may have a chromosomal-context-dependent role in gene silencing and activation decisions in mammals.

Nuclear repositioning marks the selective exclusion of lineage‐inappropriate transcription factor loci during T helper cell differentiation

“…However, mechanistic aspects are beginning to emerge: silencing can result from the juxtaposition of genes to centromeres in cis, as a result of chromosomal translocations or of the centromeric integration of transgenes [29]. Similarly, the recruitment of chromatin domains to centromeric heterochromatin in trans imposes silencing in Drosophila melanogaster [30,31], and histone modifying enzymes and polycomb proteins contribute to centromere-imposed gene silencing in D. melanogaster and in mammalian cells [31,32]. The nuclear periphery has been linked to gene silencing by correlative data in mammalian cells [33,34].…”

Deregulated MHC Class II Transactivator Expression Leads to a Strong Th2 Bias in CD4+ T Lymphocytes

“…This is reminiscent of previous studies showing variable transgene expression in T cells. For example, transgenes under the control of CD2 or lck promoters showed reduced and variable levels of expression in thymocytes (31,32). The transgenic lck promoter was active in peripheral T cells, in contrast to the endogenous lck gene (32).…”

Epigenetics and cancer

“…Three HP1 proteins are found in mammals, where HP1␣ and HP1␤ localize to pericentric heterochromatin and minor sites within euchromatin, whereas HP1␥ localizes predominantly to euchromatic regions (Eissenberg and Elgin 2000). In both mammals and flies, HP1 acts in a dosage-dependent manner with heterozygotes displaying a partial loss of gene silencing and HP1 overexpression resulting in an increase in silencing (Eissenberg et al 1992;Festenstein et al 1999). Whereas the three mammalian HP1 members all hold chromodomains capable of recognizing the methylated Lys 9 on histone H3 Lachner et al 2001), the differences in subnuclear localizations point to the presence of additional mechanisms for localizing and tethering HP1 proteins.…”