Cosmin Tudose

New paper from Narod Kebabci – “A predicted cancer dependency map for paralog pairs” www.biorxiv.org/content/10.6...

Background: The Cancer Dependency Map from @depmap.org is a fantastic resource that characterises genetic dependencies at genome-wide scale across ~1,000 cancer cell lines. 1/9

Reduced PRC2 function causes asparaginase resistance in T-ALL by decreasing WNT pathway activity Key Points. Reduced PRC2 function in T-ALL is associated with asparaginase resistance that is linked to reduced WNT/STOP pathway activity.Asparaginase resi

Great to see this out, collaboration with the Bond lab @sysbioire.bsky.social to understand consequences of EZH2 mutation in T-acute lymphoblastic leukaemia (T-ALL). Congrats to @lefeivret.bsky.social @cosmintudose.bsky.social and other authors not on bluesky!

ashpublications.org/bloodadvance...

Finally, thanks to @researchireland.ie, CRT Genomics Data science for funding this work! And thanks to @ucddublin.bsky.social @sysbioire.bsky.social for the support offered! 17/17

Thanks to my supervisors for guiding this work Jonathan Bond and @colmr.bsky.social and to everyone involved for all the important and hard work put in Luke Jones, Claire Fitzgerald, @tgrosu.bsky.social, @nmaziak.bsky.social Rebecca Ling, @roylab-oxford.bsky.social, @vaquerizasjm.bsky.social 16/17

...leading to partial activation of an onco-fetal LIN28B-driven program that makes AML cells more resistant to CDK6 inhibition. 15/17

Our work highlights the role of polycomb in guiding the expression of lineage-defining transcriptional programs and heterozygous loss of EZH2 is enough to blur the lines between transcriptional programs…🌫️14/17

Finally, we found that the EZH2-LIN28B-CDK6 axis leads to increased resistance to the CDK4/6 inhibitor palbociclib. 13/17

LIN28B is rarely expressed in normal adult cells, but is active in >20 cancer types, including leukemias. As part of this program we find the cyclin-dependent kinase CDK6, which shows decreased promoter H3K27me3, accompanied by increased H3K27ac and increased transcription. 12/17

Finally, we found that our EZH2+/- cells show activation of an alternative lineage transcriptomic program associated with LIN28B activation. Using RNA-seq from LIN28B-KD CD34+ fetal liver cells, we confirmed that EZH2-depleted cells are consistent with LIN28B activation. 11/17

Notably, we observed a compartmentalization change upstream of the LIN28B locus in the Hi-C data. While this locus did not show any significant change in H3K27me or H3K27ac, the LIN28B fetal oncogene was upregulated in our EZH2+/- cells. 10/17

Secondly, as observed in the Hi-C, these peaks are found in regions where there is high DNA-DNA contact frequency in all conditions, suggesting H3K27me3 is preferentially maintained at these hubs of compacted chromatin ➰➰➰. 9/17

Naturally, we observed that some level of H3K27me3 is maintained in EZH2+/- and we found out that these maintained me3 peaks show distinctive characteristics. Firstly, these peaks are wider, covering a larger genomic area🧬. 8/17

Changes in chromatin accessibility are not concordant with transcriptional changes for single‐factor perturbations | Molecular Systems Biology image image Systematic analysis of tandem, bulk ATAC‐seq and RNA‐seq measurements from cells exposed to single‐factor perturbations shows two groups of genes: those with concordance between accessibility and expression changes and those ...

However, the relationship between chromatin accessibility and transcriptional activation is complex. As previously shown by Kiani et al. (doi.org/10.15252/msb...), increased chromatin accessibility does not always lead to transcription. 7/17

Again, we observed that regions with increased accessibility were enriched for GO terms relating to cell differentiation and alternative transcriptional lineages. 6/17

As expected, we observed genome-wide decrease in the PRC2-mark H3K27me3, accompanied by increased H3K27ac and increased chromatin accessibility. NOTE: C5 and C9 are EZH2+/- cells in the figure below. 5/17

This suggests that PRC2 depletion leads to transcriptional changes related to cell differentiation. But what about direct epigenetic changes?🤔 4/17

Strikingly, we observed that at the transcriptomic level the PRC2-depleted showed increased expression of genes typically expressed monocytic-dendritic progenitors (e.g., CDCA7, CDK6), and decreased expression of genes expressed in mature monocytes (e.g., ITGAM, S100A12)🩸. 3/17

We generated a PRC2-depleted model by heterozygously targeting the catalytic component EZH2✍️in OCI-AML2 cells🧫. We then extensively characterized these cells by RNA-Seq, ATAC-Seq, CUT&RUN and Hi-C. 2/17

Diverse epigenomic mechanisms underpin transcriptional dysregulation in Polycomb-altered acute myeloid leukemia Background Polycomb Repressive Complex 2 (PRC2) modulates chromatin accessibility and architecture to direct tissue-specific gene expression. PRC2 function is frequently altered in cancer by loss-of-f...

Pleased that the 2nd part of my PhD is now available as a preprint! Here, we investigated the epigenomic and transcriptomic changes occurring upon PRC2 depletion in AML cells. biorxiv.org/content/10.1.... A thread🧵1/17