Through a genetic screen, we identified the inner nuclear membrane protein Lem2 as a critical factor in heterochromatin silencing (Barrales et al. Genes Dev 2016; Braun & Barrales. Nucleus 2016). Lem2 belongs to the family of LEM domain-containing proteins, which are conserved from yeast to humans and known to contribute to the perinuclear tethering of chromatin. In metazoans, the LEM domain interacts with non-sequence specific DNA-binding factors during post-mitotic nuclear membrane assembly; however, its role in gene silencing and heterochromatin localization has remained elusive. Through systematic genetic interaction studies using SGA we found that Lem2 is part of a network of multiple redundant silencing pathways, including the RNAi machinery. These pathways have in common that they largely originate from the nuclear periphery, illustrating the prominent role of the nuclear periphery in gene repression. We further demonstrated that the LEM domain of Lem2 associates with centromeric chromatin and mediates its recruitment to the nuclear periphery. Yet unexpectedly, silencing by Lem2 is independent of its LEM domain but requires its C-terminal MSC domain. This domain also controls telomere tethering at the nuclear periphery. Thus, centromere localization, telomere anchoring and silencing, while mediated through the same protein, can be mechanistically separated. These findings reveal an unanticipated complexity and shift the focus from the well-studied LEM domain to the poorly understood MSC domain. We are currently testing the hypothesis that Lem2’s repressive role is mediated through the recruitment of soluble factors to its MSC domain.

  • Research overview [back]
  • Project (1) Identifying novel factors and dissecting regulatory networks [read more]
  • Project (2) Demarcation and protection of heterochromatin domains [read more]
  • Project (3) Regulation at the periphery