🚨New Preprint 🚨: What are the key epigenetic mechanisms that drive species-specific gene regulation during primate neurogenesis — and how do they contribute to the evolution of the human neocortex? .Curious? 👇.Led by Silvia Vangelisti @sinsy_ and Boyan.

Congratulations, Jei! 🎉.We’re so proud of your journey and all that you’ve achieved. Thank you for all your incredible contributions! 🎓.

This was a great collaboration between the @BonevLab and the Tanay Lab, led by @yonatan1shapira and @FNoack86 with substantial contribution from @sinsy_, @fayeeeC_ and @aviezer_l. If you found this study of interest, please RT, comment and share! All feedback is welcome. 14/14.

Code and data to reproduce all figures, or browse and reanalyze, is available at either separately or in a standalone docker container. You can also explore the data interactively at 13/14.

Finally, we assayed the activity of thousands of CREs isolated from their genomic context across multiple timepoints in vivo using a cell-type-specific MPRA. This assay showed that cell type-specificity is encoded in the sequence, in agreement with our quantitative model. 12/14

We also show explicitly that NSC methylation has a repressive effect on IPC accessibility, and that cooperativity between proximal CREs is correlated with accessibility both in terms of sequence content and total proximal activation. 11/14

We developed a machine-learning model that integrates sequence (putative TF motifs, dinucleotide content) and epigenomic features (ATAC, methylation, proximal activity) to predict NSC<->IPC specificity of CREs, that yields R^2 = 0.62 on held-out data. 10/14

Moreover, temporally activating CREs in NSCs get compacted significantly closer over time to astrocyte- or NSC-specific TSSs, an effect not observed with IPC TSSs. 9/14

Our Hi-C analysis shows that while overall chromatin topology is conserved across time in NSCs, there are specific hotspots whose differential insulation across time is correlated with the presence or depletion of proximal CREs. 8/14

Temporally activating CREs are significant: they are enriched with astrocyte-specific CREs, and astro CREs undergo extensive demethylation within NSCs across time, in contrast to other cell type-specific CREs. 7/14

We found that ATAC-activating CREs are tightly concomitant with methylation decrease. But the opposite was not true! Deactivating CREs in NSCs stay unmethylated across our time series, and this is not due to absence of DNMTs. 6/14

Furthermore, we were able to identify CREs with dynamic accessibility within cell types, across time. We focused on CREs that either activate/increase accessibility, or deactivate over time in NSCs. 5/14

Our metacell model of ATAC states provides a high-resolution timeline of CRE accessibility in corticogenesis. We use it to show that CREs specific to corticofugal neurons are activated late in maturation, in stark contrast to callosal projection neuron-specific CREs. 4/14

We show that astrocyte genes in NSCs are upregulated gradually over time, not suddenly, along with erosion of NSC proliferative capacity. This erosion is also correlated with lengthening of the cell cycle, suggesting that NSC fate bias is coupled to the cell cycle. 3/14

We have generated one of the most comprehensive multiome datasets in the context of brain development, integrating time-series measurements of scRNA-seq, scATAC-seq, 5mC methylation and Hi-C of mouse somatosensory cortex across 6 developmental timepoints. 2/14

Can a stem cell change its epigenome while proliferating? In our new preprint, in collaboration with the Tanay Lab, we demonstrate that the epigenome of neural stem cells is continuously remodeled, across multiple layers, during mouse corticogenesis. 1/14

RT @sinsy_: Very happy to share the preprint of my main PhD project in the @Bonev_Lab! Huge thanks to Boyan, all co-authors and members of….

This study was led by @sinsy_, with contributions from @fayeeeC_ , Tamina Dietl, Sebastian Diecke, and Wolfgang Enard — a great collaboration with @EnardHellmannWG ! Congrats to all!.

7/7 By combining multi-omic profiling with state-of-the-art computational analysis, we link 3D epigenome evolution to transcriptomic changes in primate brain development, revealing how divergent regulatory networks and epigenome dynamics contribute to human brain evolution.

6/7 Species-specific genes were often associated with multiple differentially accessible regions, suggesting that synergistic enhancer activation is a key mechanism driving epigenome evolution.

5/7 High-resolution Hi-C revealed unexpected global shifts in 3D genome architecture in the chimpanzee and gorilla NSC, while topologically associating domains remain remarkably conserved.