Cosmin Tudose
@cosmint_
Followers
203
Following
888
Media
20
Statuses
118
Pleased that the 2nd part of my PhD in now available as a preprint! Here, we investigated the epigenomic and transcriptomic changes occurring upon PRC2 depletion in AML cells. https://t.co/xc0v6DUXW3. A thread🧵1/17
biorxiv.org
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-o...
2
4
12
Finally, thanks to @Researchirel @GenomicsCRT @MSCActions for funding this work! And thanks to @ucddublin @UCDMedicine @sysbioire for the support offered. 17/17
0
0
2
Thanks to my supervisors for guiding this work @jbond2019 @colmr and to everyone involved for all the important and hard work put in @iamnotaprawn @TheodoraGrosu @ClaireFitzG18 Noura Maziak, Rebecca Ling, @andiroy, @vaquerizasjm. 16/17
1
0
2
...leading to partial activation of an onco-fetal LIN28B-driven program that makes AML cells more resistant to CDK6 inhibition. 15/17
1
0
0
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
1
0
0
Finally, we found that the EZH2-LIN28B-CDK6 axis leads to increased resistance to the CDK4/6 inhibitor palbociclib. 13/17
1
0
0
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
1
0
0
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
1
0
0
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
1
0
0
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
1
0
0
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
1
0
0
However, the relationship between chromatin accessibility and transcriptional activation is complex. As previously shown by Kiani et al ( https://t.co/e1V368ov9S), increased chromatin accessibility does not always lead to transcription. 7/17
embopress.org
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 accessi...
1
0
0
Again, we observed that regions with increased accessibility were enriched for GO terms relating to cell differentiation and alternative transcriptional lineages. 6/17
1
0
0
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
1
0
0
This suggests that PRC2 depletion leads to transcriptional changes related to cell differentiation. But what about direct epigenetic changes?🤔 4/17
1
0
0
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
1
0
0
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
1
0
0
New data from our group! Working with Kholodenko/Rukhlenko groups @sysbioire we used structure-based modelling to find novel non-expected AML drug combos, which we validated in vivo. Huge thanks to @IrishCancerSoc for funding Luke Jones @iamnotaprawn
biorxiv.org
Mutations activating RAS/RAF/MEK/ERK signaling are associated with poor outcome in acute myeloid leukemia (AML), but therapeutic targeting of this pathway is challenging. Here, we employ a structur...
0
7
21
Many thanks to my supervisors @jbond2019 and @colmr, to everyone in @sysbioire and to the @GenomicsCRT! :)
Congratulations to Cosmin Tudose on passing his viva yesterday! 🥂🎉 Cosmin is co-supervised by @colmr & @jbond2019 funded by @GenomicsCRT. Thesis title: "Defining molecular vulnerabilities in childhood leukaemia through biological network analysis". Well done @cosmint_! #viva
3
1
33
Congrats to Gold Medal Runner Up @cosmint_ 👏 🎉 His study shows that Gene expression is a better predictor of cancer cell sensitivity to treatments than gene regulatory networks. 🔍 #conwayfest24 #CancerResearch #Genomics #CRISPR
0
7
21