iiinova — where your digital self keeps evolving

Reposted by Sunniyat Rahman

James Davies @jojdavies.bsky.social · 05/11/2025

Our latest paper has just been published in Cell! doi.org/10.1016/j.ce... We developed a new method called MCC ultra, which allows 3D chromatin structure to be visualised with a 1 base pair pixel size.

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Sunniyat Rahman @minimolecule.bsky.social · 18/04/2025

Congrats Nicola, brilliant work!

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Reposted by Sunniyat Rahman

Nicola Maciocia @nicolamaciocia.bsky.social · 17/04/2025

Starting off my bluesky journey by sharing my paper published this week: CD21 targeted CAR-T cells for the treatment of T-ALL. The result of many years of work from many people. Funded by #CRUK #UKRI MRC and #GOSHCC www.science.org/doi/10.1126/...

science.org

Preclinical development of anti-CD21 chimeric antigen receptor T cells to treat T cell acute lymphoblastic leukemia

Fratricide-resistant anti-CD21 CAR-T cells are effective in preclinical models of T cell acute lymphoblastic leukemia (T-ALL).

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Sunniyat Rahman @minimolecule.bsky.social · 06/01/2025

My previous mentor and great friend Prof. Marc Mansour from UCL has joined Bluesky! 🎉 Do consider following him if you’re researching acute leukaemias and associated novel therapies! bsky.app/profile/marc...

bsky.app

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Reposted by Sunniyat Rahman

The Dawson Lab @thedawsonlab.bsky.social · 15/12/2024

Check out our new pre-print! Exciting times ahead for Menin biology and targeting epigenetics regulators in AML. Congratulations to all involved!

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

Thanks Marina, too kind. Such fond memories of those committee meetings...those were the days... 💙

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

This research was funded by Leukaemia UK, @cancerresearchuk.org, GOSH Charity and others. None of these discoveries would be possible without the support and consent from patients and their families. This discovery is for them.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

A huge thanks to all collaborators involved for their expert input, most haven't come over to 🦋 as yet bar the wonderful @adelekfielding.bsky.social

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

I want to highlight the incredible support of @mafdawson.bsky.social who has welcomed me into his lab at a critical point in my academic career and my previous mentor Prof. Marc Mansour (UCL) for his advice and guidance on this project and beyond.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

A special thanks to the incredibly talented Gianna Bloye who completed critical parts of this paper and is now doing her PhD @ox.ac.uk. And to Nadine Farah (UCL) and Jonas Demeulemeester (VIB-KU) who have been on this challenging expedition with me to find cis-acting noncoding mutations in T-ALL.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

We speculate that ‘promoter tethering’ of oncogenes to inert regions of the genome is a previously unappreciated mechanism preventing tumorigenesis, and postulate similar mechanisms may be found in other cancers.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

These findings also add to the complex regulatory relationship between the FTO and IRX3 genes, first identified through the discovery of obesity-associated germline variants.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

This mechanism differs to previously described enhancer hijack events, which bring enhancers and promoters together through structural rearrangement. And differs to examples of focal deletions that impinge on TAD boundaries as we believe this all happens intra-TAD.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

These data suggest IRX3 is sequestered to FTO intron 8 through a ‘promoter tether’ facilitated by CTCF. Loss of this CTCF site by focal deletion untethers the IRX3 promoter allowing for enhancer hijack. This may be an example of E-P competition occurring within the same TAD.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

By using CRISPR/Cas9 we disrupted the CRNDE super-enhancer in FTO intron 8 CTCF site deleted cells (ALLSIL). This led to a significant reduction in IRX3 expression, meaning this super-enhancer is indeed hijacked by IRX3.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

So what’s the deal with CRNDE? It encodes for a lncRNA that is actively transcribed throughout T cell development and harbours a super-enhancer. HiChIP shows this super-enhancer loops to IRX3 suggesting its hijacked in FTO intron 8 CTCF site deleted T-ALL cells (ALLSIL)

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

We also baited the IRX3 promoter in our CRISPR/Cas9 edited cells (PF382) with and without the FTO intron 8 CTCF site, observing the same effect of increased contacts with the CRNDE region along with increased transcriptional output of IRX3.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

In contrast doing the same with FTO intron 8 CTCF site deleted cells (ALLSIL) massively increased the contacts between the IRX3 promoter and CRNDE along with transcriptional activation of IRX3. Look at the contact delta 👆(above)

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

With UMI-4C we baited the CTCF site in FTO wild-type cells (PF382). This showed that IRX3 is ‘tethered’ to FTO intron 8. In the same cells we baited the IRX3 promoter which identified minimal contacts with CRNDE with no transcriptional output of IRX3.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

So what does the FTO intron 8 CTCF site usually do? 🤔

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

CRISPR/Cas9-mediated deletion of the FTO intron 8 CTCF site in IRX3 negative (PF382) T-ALL cells transcriptionally activated IRX3 in single cell sorted clones and polyclonal populations, with no activation if you only delete the MYB site. This suggested the CTCF site was critical.

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

Whilst most patients had copy number loss for both CTCF and MYB sites, 4/12 had heterozygous copy number loss of the CTCF site alone, suggesting that loss of this CTCF site was more likely to be functionally relevant. But do the deletions transcriptionally activate IRX3?

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

By using ddPCR probes against the CTCF and MYB sites we identified CN deletions in a site-specific manner. This showed FTO intron 8 deletions occur in 1.5% of adults and 6.2% of paediatric patients with T-ALL. But have a look at the site-specific calls👀

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

Amazingly these deletions defined a minimal region of ~155kb. ChIP-seq data from a T-ALL cell line identified CTCF binding and a MYB bound enhancer within this region. Both CTCF and MYB have previously been implicated in mechanisms of aberrant gene expression in T-ALL

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

Expression data was available for 6/13 T-ALL samples showing these were IRX3+ by RNAseq. Notably, 1 patient exhibited allele specific expression supporting our working hypothesis that IRX3 expression may be driven by a cis-acting genetic lesion

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

By studying published genomic datasets from primary T-ALL patient samples and T-ALL cell lines we identified 13 T-ALL genomes (12 from patients and 1 cell line) with heterozygous copy number losses impinging on FTO intron 8 – the 3’ contact point to IRX3

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

IRX3 sits in a single TAD with neighbouring genes FTO, CRNDE and IRX5. HiChIP data from an IRX3 positive cell line identified contacts 3’ to IRX3 within FTO intron 8, and 5’ to IRX3 within the CRNDE/IRX5 locus. We thought these two contact points may hold the clue…

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

IRX3 is not expressed in normal T-cells. But high IRX3 expression is a feature of T-ALL and observed across differing molecular subtypes of T-ALL. Special mention to Somervaille Lab @cruk-mi.bsky.social who have previously shown it can cause T-ALL in vivo. The question is what’s driving this?

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

Link here to the manuscript if you want to get right into it, or carry on to the thread below. If you're into gene-regulation and/or noncoding mutations this may be of particular interest! (Note: I'm bringing this thread over from the other place).

ashpublications.org

Focal deletions of a promoter tether activate the IRX3 oncogene in T-cell acute lymphoblastic leukemia

Key PointsRecurrent focal deletions of a CTCF-binding site within FTO intron 8 occur in 1.5% of adult and 6.2% of pediatric patients with T-ALL.Focal delet

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Sunniyat Rahman @minimolecule.bsky.social · 10/12/2024

For my new followers! Focal deletions of noncoding regions in cancer genomes can have unexpected consequences. Out now in @bloodjournal.bsky.social, we’ve discovered a novel mechanism of oncogene activation whereby focal deletion of a ‘promoter tether’ leads to aberrant expression of IRX3 in T-ALL.👇

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Reposted by Sunniyat Rahman

Dineika Chandra @dineika-chandra.bsky.social · 06/12/2024

Plugging our new paper on the new platform: “Unravelling mutational signatures with plasma circulating tumour DNA”

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Reposted by Sunniyat Rahman

Olivier Saulnier @olivier-saulnier.bsky.social · 24/11/2024

Let's build a starter pack for childhood cancer research. Please send a message to be added! 🎗️ go.bsky.app/Tpd9QnM

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Sunniyat Rahman @minimolecule.bsky.social · 24/11/2024

Thanks for making this Olivier, please may I be added to this, thanks!

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Sunniyat Rahman @minimolecule.bsky.social · 21/11/2024

Here’s one that may be of interest, I think there is also a sequel to this one too! go.bsky.app/5zgpZfg

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Reposted by Sunniyat Rahman

Peter MacCallum Cancer Centre @petermaccc.bsky.social · 21/11/2024

Peter Mac is excited to join BlueSky! 🦋 We look forward to sharing ideas, fostering positivity, and connecting with you all as we work together to advance cancer care and research. Let’s inspire, collaborate, and make a difference!

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Reposted by Sunniyat Rahman

Mark Dawson @mafdawson.bsky.social · 18/11/2024

A social media platform where likeminded individuals (not trolls or imbeciles) interact to share their latest ideas, discoveries and news - Looking forward to this!

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Reposted by Sunniyat Rahman

Sarah-Jane Dawson @sj-dawson.bsky.social · 18/11/2024

Looking forward to joining the Bluesky community- glad to have made the move!

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Sunniyat Rahman @minimolecule.bsky.social · 17/11/2024

We gotta give the people what they want 😉 I’ll pitch it to him when I see him today 👍

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Sunniyat Rahman @minimolecule.bsky.social · 16/11/2024

Thank you for making this, would love to be added to this pack 🙂

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Sunniyat Rahman @minimolecule.bsky.social · 14/11/2024

Ha you’re amazing, thanks for adding me Dorien 😉 great to see you here too! Will try my best to keep connecting with peeps!

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Sunniyat Rahman @minimolecule.bsky.social · 14/11/2024

Thanks Piotr, would love to join this too🙂

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Sunniyat Rahman @minimolecule.bsky.social · 14/11/2024

Hey scientists/academics👋, I’m moving over. Looking to follow researchers working on gene regulation, epigenetics, lineage tracing, non-coding mutations, single cell techniques, and drug resistance in cancer - let’s follow each other 😄

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