The majority of the human genome contains transcriptionally inactive heterochromatin and only 20% actively transcribed euchromatin. The epigenetic landscape of heterochromatin and euchromatin is different and marked by defined modifications. In order to promote heritable transmission of gene expression states, epigenetic modifications have to be faithfully restored after cell division. Except for DNA methylation, the mechanisms involved in recapitulating the parental chromatin structure are

more »

... defined. It is known for over 50 years that heterochromatin is in close contact with the nuclear lamina. Yet, genome-wide mechanisms and the regulatory principles underlying peripheral heterochromatin are largely unknown. The aim of this thesis is to elucidate these mechanisms of heterochromatin maintenance at the nuclear lamina. We investigated the contributions of lamin and SUN proteins in the maintenance of heterochromatin. For that, we are using a Chromatin in vivo Assay which allows us to artificial silence a reporter gene. We generated loss-of-function and truncated mutant cell lines, via CRISPR-Cas9. We systematically characterized LMNB and SUN2 cell lines in our reporter assay. This revealed that a loss-of-function LMNB2 mutant was unable to reactivate the reporter gene. Additionally, we obtained a significant increase of reactivating cells in a truncated mutant cell line of LMNB1. Surprisingly, we demonstrate for the first time that SUN2 specifically contributes to an epigenetic inheritance of heterochromatin. In summary, these data support evidence that the nuclear periphery influences heterochromatin maintenance. This opens future perspectives to understand heterochromatin maintenance in mechanistic and molecular details.