… We squeezed in some other important scientific activities too 👀

Pin the primitive streak on the embryo (blindfolded) at lab retreat! They did pretty well… except maybe one who seemed to think it was a Lefty1 mutant 👈 😀

Incredible night for Italy at the European championships - 3 golds 🏅… nuts view for Marcel Jacob’s in 100m

Finally, we also tested how chromatin marks interact with each other by exploiting our system for combinatorial epigenetic editing. For example, H3K27me3 and H2AK119ub function additively Combinatorial marks thus confer robustness of response at single-cell level

Is this relevant at endogenous genes?... KO+Epi-editing shows promoter H3K36me3 represses Xist - but not if CTCF motif is deleted Context-dependency is critical Understanding these relationships is key to functionally interpret (epi)genomics profiles in health and disease

What about context? How does underlying DNA sequence functionally interact with chromatin marks. A lot. For example, H3K36me3 is only very weakly effective BUT in the presence of a CTCF motif, H3K36me3 now switches behaviour to become a powerful transcription repressor

Putting H3K4me3 back to promoters that lost it in Mll2 mutants by targeted epigenetic editing restores their expression H3K4me3 has the *potential* to directly promote transcription (assuming appropriate TF are present)

Somewhat surprisingly (to us), installing de novo H3K4me3 using independent effectors – but not CM controls – triggered transcription upregulation Reciprocally, specific loss of H3K4me3 by homozygous Mll2 point-mutants led to downregulation 👇

We capture that installation of most marks triggers at least some quantitative expression response at the single cell level For example, programming polycomb mark H2AK119ub (red) directly drives repression. BUT a catalytic-mutant (CM) control (blue) has negligible effect