@steffenfuchs.bsky.social , let’s go for a 3rd round!

Thanks to David Juan, Daniel Rico, and Enrique Carrillo for the initial ChAs framework and for discussions on this project, to Emanuele Raineri for co-developing ChAseR and to Simone Ecker for fundamental discussions on gene expression variability that led to this.

But does this have any relevance in solid tumours? Hard to say due to lack of data, but some of our findings might hold (see supplementary material).

In brief, we reveal distinct genome spatial patterns associated with gene evolutionary ages. We suggest that RNA PolII facilitates old UC genes’ preferential interactions. Polycomb regulation of EM genes is largely lost in cancer, where MM genes may cluster at the periphery.

Old UC genes have preferential interactions in all 3 cell states. EM genes have reduced preferential interactions in cancer. New genes acquire some preferential interactions only in cancer, potentially mediated by the lamina at the nuclear periphery.

We used chromatin assortativity (ChAs) analysis to quantify clustering patterns of genes with specific characteristics. Read this paper to know more about the ChAseR tool to perform this analysis (Madrid-Mencia et al. 2020 shorturl.at/Ax73E).

Polycomb is key for 3D chromatin structure (Pancaldi et al. 2016 shorturl.at/YEOQr). So we looked at spatial organisation of genes of specific evolutionary ages finding preferential interactions on 3D promoter-centred chromatin networks.

We analysed differentiation and oncogenesis with 3 cell types: stem, differentiated, and cancer (hESC, B cells, and CLL, a B-cell lymphoma). RNA PolII Pausing regulates primarily old UC genes, especially in normal B cells, in which Polycomb targets the highest gene percentage.

Combining ChIP-seq and DNA methylation datasets in monocytes we see different regulation: Polycombs preferentially regulates intermediate EM genes, and DNA methylation regulates mainly recent MM genes.

Second: in monocytes the Polycomb, H3K27me3 repressive mark shows a higher enrichment around intermediate EM genes, than around old UC and young MM genes.

First: gene expression and expression variability across individuals are strongly associated with evolutionary ages in 3 immune cell types, old UC genes - low variability, recent EM genes - high variability

We studied gene regulation and 3D organisation across 16 evolutionary ages, further grouped into three classes: UC (Unicellular genes), EM (Early metazoan genes), and MM (Mammalian-specific genes) as in Trigos et al. 2017 tinyurl.com/yvwwja2s

Old genes are often highly expressed in cancer, while newer genes tend to be repressed. However, the underlying mechanisms were never explored.