Figure 1: Multiple developmental abnormalities and pervasive apoptosis (blue cells) in mouse embryos disrupted for Fbxl10, a transcription factor that defends promoters against de novo DNA methylation.
Figure 2: Representative ChIP-seq data showing high occupancy of O-GlcNAcylated proteins and trimethylation of lysine 9 of histone H3 (H3K9me3) at retrotransposons of the IAPEz family that is responsible for about 40% of all transposon mutations in inbred mice. The SHIN domain bound by glycosylated proteins is sufficient to trigger heterochromatinization.
The Boulard group combines mouse genetics with biochemical and genomic approaches to study how mammalian cells stably repress parts of their genome.
Previous and current research
Our group studies how the genetic information can be interpreted differently across cell types and time. We are particularly interested in understanding how mammalian cells regulate the availability of their genome by repressing specific genes. This biological process, commonly referred as epigenetic gene silencing, plays a crucial role in sexual reproduction by controlling the expression of mono-allelically expressed genes (i.e. Imprinted genes and genes of the X-inactive chromosome in female cells). Furthermore, epigenetic silencing is essential to preserve genomic integrity by repressing permanently genomic parasites such as retrotransposons. The repressive state at specific loci is instructed by cytosine methylation, a mitotically transmitted chemical modification of the DNA. Despite our detailed knowledge of the biochemical systems that regulate DNA methylation patterns, the mechanism of transcriptional silencing of methylated promoters remains enigmatic. Our recent work on the silencing mechanism of endogenous retroviruses revealed the surprising importance of the glycosylation, a reversible post-translational modification of intra-cellular proteins by the sugar β-D-N-acetylglucosamine (O-GlcNAc).
Future projects and goals
We will continue to explore the molecular basis of chromatin-based gene regulation focusing on two fundamental questions: i) What is the cellular readout of genomic methylation in specific sequence contexts? and ii) How does chromatin glycosylation regulate gene expression? We will address these challenges in vivo using mouse genetics as a mammalian model organism. We will integrate multidisciplinary approaches including genetics, optogenetics, traditional and specially resolved transcriptomics, microscopy and proteomics.