Do histone modifications mediate epigenetic memory of transcription states?Daniel Holoch (Genetics and Developmental Biology, Institut Curie)
Daniel Holoch carried out his doctoral studies in the lab of Danesh Moazed at Harvard University, where he studied how small RNAs are loaded onto Argonaute in Schizosaccharomyces pombe and discovered that conserved GW-repeat-containing interactors of Argonaute proteins act as critical sensors of small-RNA loading status (Holoch and Moazed, Nat. Struct. Mol. Biol., 2015). He then joined Raphaël Margueron’s lab at the Institut Curie in 2016 for his postdoc to examine the role of histone modifications in the epigenetic memory of transcription states in mammals. It is sometimes taken for granted that histone modifications are faithfully copied during genome replication, and that this is important for the memory of active and inactive transcription states at individual genes. Using histone H3 lysine 27 trimethylation (H3K27me3) by Polycomb Repressive Complex 2 (PRC2) as a model, he found that this histone modification indeed enables a local, cis-acting memory of transcription states, but not through the classical copy-and-paste mechanism previously envisioned by the field. Indeed, existing H3K27me3 does not appear to be generally necessary for guiding new PRC2 activity. Instead, epigenetic memory requires conditions in which PRC2 and activating transcription factors are in a balanced competition for access to a gene, allowing transient signals to trigger lasting switches between two self-stabilizing transcription states. Genome-wide analyses, locus-directed manipulations and computational modeling they have conducted all support these conclusions (Holoch*, Wassef* et al., Nat. Genet., 2021). His ongoing investigations aim to understand why pluripotent stem cells appear to lack this form of PRC2-dependent epigenetic memory, as well as the degree to which long-lasting memory of transient transcription events extends beyond genes controlled by PRC2.
Daniel Holoch is invited by Djihad Hadjadj.