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Reposted by James Nolan

Chen Davidovich @davidovichlab.bsky.social · 31/10/2025

1/ It's long been assumed that AEBP2 recruit PRC2 to chromatin. Now, we show that AEBP2 usually does the exact opposite: The only isoform of AEBP2 that is expressed in most cell types and tissues inhibits the chromatin-binding activity of PRC2. www.embopress.org/doi/full/10....

embopress.org

Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2 | The EMBO Journal

imageimageAEBP2 is an accessory subunit of the PRC2 complex previously implicated both in promoting and antagonizing Polycomb repressive activity. This study reveals that its alternative isoforms, AEB...

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Reposted by James Nolan

Adrian Bracken @adrianbracken.bsky.social · 31/10/2025

1/ 🚀 AEBP2 isn’t what we thought. You were told that AEBP2 promotes PRC2 activity on chromatin. We found the opposite: the most prevalent AEBP2 isoform inhibits PRC2 activity. 👉 surl.li/cgwqcq A thread 🧵

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James Nolan @jamesnolan.bsky.social · 18/10/2025

Thank you especially to PI Prof Michael Crump, co-authors in the LMT Group (Prof John Kuruvilla , Dr Anca Prica, Dr Abi Vijenthira, Dr Sita Bhella, Dr Robert Kridel), GU Group (Prof Philippe Bedard , Dr Di Maria Jiang, Dr Esmail Al-Ezzie, Dr Robert Hamilyon), Prof Pádraig Warde & Prof Malcolm Moore

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James Nolan @jamesnolan.bsky.social · 18/10/2025

Despite favourable data for cohort overall, patients with platinum refractory disease prior to ASCT had a PFS of <6 months, highlighting a population with a significant unmet need for alternative strategies

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James Nolan @jamesnolan.bsky.social · 18/10/2025

A total of 123 transplants completed. With median 6.4 year follow-up, median PFS/OS not reached with 2-year PFS and OS 52.1% and 73.4%. No progression events after 2 years.

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James Nolan @jamesnolan.bsky.social · 18/10/2025

Pleased to present at #ESMO25 the 16 year experience of tandem high-dose chemotherapy and autologous stem cell transplant for relapsed/refractory advanced stage germ cell tumours from Princess Margaret Cancer Centre, Toronto 🇨🇦

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James Nolan @jamesnolan.bsky.social · 17/10/2025

16/ This work complements our previous research on CBX4 and H3K27M-mutant DMG [tinyurl.com/ev6drrya], showing how different forms of PRC2 dysfunction can be targeted in distinct cancer contexts. 🔍

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James Nolan @jamesnolan.bsky.social · 17/10/2025

15/ We believe our findings offer significant insights for both basic and clinical research. By understanding the role of H3K27me2 in PRC2 dysfunction, we can explore new treatments for EZH2-dependent cancers. 🏥

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James Nolan @jamesnolan.bsky.social · 17/10/2025

14/ In fact, we also show that targeting AEBP2 can overcome two distinct mechanisms of resistance to EZH2 inhibitors in vitro, a finding with important therapeutic implications. 💊

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James Nolan @jamesnolan.bsky.social · 17/10/2025

13/ Why does this matter? Our study reveals how AEBP2 regulates H3K27me2 at intergenic regions, offering a new view of PRC2 dysfunction in cancer. This provides new therapeutic opportunities by targeting AEBP2 in cancers resistant to PRC2 inhibitors! 💡

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James Nolan @jamesnolan.bsky.social · 17/10/2025

12/ AEBP2 likely acts downstream of PCGF5 (a variant PRC1 member), which is responsible for depositing H2AK119ub1 at intergenic regions. Interestingly, we also show that PCGF5 loss also sensitizes cells to PRC2 inhibitors. 🔄

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James Nolan @jamesnolan.bsky.social · 17/10/2025

11/ Mechanistically, we show that the ZF2 domain of AEBP2 is essential for its ability to bind chromatin and promote PRC2 mediated H3K27me2 at intergenic regions.

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James Nolan @jamesnolan.bsky.social · 17/10/2025

10 / We used sgRNA-tiled CRISPR screens to pinpoint the 3 zinc fingers of AEBP2 as being essential for its function in EZH2-mutant lymphoma! 🧬

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James Nolan @jamesnolan.bsky.social · 17/10/2025

9/ Mechanistically, in lymphoma, AEBP2 functions within a unique PRC2.2 complex that lacks JARID2, making it less tethered to CpG islands at Polycomb target genes.

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James Nolan @jamesnolan.bsky.social · 17/10/2025

8/ Our key finding: H3K27me2 is central to both sensitivity and resistance to PRC2 inhibitors. Loss of NSD2 increases H3K27me2, while loss of AEBP2 reduces it in EZH2-mutant lymphoma. This could explain why some cancers are resistant to treatment. ⚖️

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James Nolan @jamesnolan.bsky.social · 17/10/2025

7/ We also found that loss of NSD2 (responsible for mediating H3K36me2) increases H3K27me3 yet, unlike loss of AEBP2, its loss confers resistance to PRC2 inhibitors. This led us to focus on the underexplored H3K27me2 modification! 🔬

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James Nolan @jamesnolan.bsky.social · 17/10/2025

6/ Unlike loss of core PRC2 components, the loss of AEBP2 increases H3K27me3 levels without derepressing Polycomb target genes. AEBP2 acts differently from other PRC2 components in regulating chromatin, making it an exciting new target in cancer. 🧫

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James Nolan @jamesnolan.bsky.social · 17/10/2025

5/ We identified the PRC2 accessory component AEBP2 as a genetic dependency in EZH2-mutant lymphoma via a CRISPR screen, but interestingly, this dependency isn't observed in other PRC2-dependent cancers such as malignant rhabdoid tumors or H3K27M-mutant DMG [tinyurl.com/ev6drrya].

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James Nolan @jamesnolan.bsky.social · 17/10/2025

4/ In this study, we discover a new form of PRC2 dysfunction in cancer - distinct from canonical PRC2-mediated H3K27me3 associated repression - that modulates sensitivity and resistance to PRC2 inhibitors. Specifically, we find it involves deregulation of H3K27me2 at intergenic chromatin regions. 🧬

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James Nolan @jamesnolan.bsky.social · 17/10/2025

3/ Thanks to many others across @tcddublin.bsky.social, @ucddublin.bsky.social, @uniofgalway.bsky.social, @mayoclinic.org, and Trinity St. James’s Cancer Institute, and to our generous funders Irish Cancer Society and @worldwidecancer.bsky.social.

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James Nolan @jamesnolan.bsky.social · 17/10/2025

2/ Firstly, this was a fantastic collaborative effort that would not have been possible without super-talented co-first author @dr-chromatin.bsky.social, and co-senior authors @conwayer1.bsky.social and @adrianbracken.bsky.social.

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Reposted by James Nolan

Eimear Lagan @eimearlagan.bsky.social · 21/05/2025

Excited to share our new paper out today in @cp-molcell.bsky.social! We show that the H3K27M oncohistone rewires cPRC1, creating a unique dependency on CBX4/PCGF4-containing complexes, and also reveal a previously unknown function of CBX4. Highlights below (1/11).

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Reposted by James Nolan

dairegannon.bsky.social @dairegannon.bsky.social · 21/05/2025

Our work identifying CBX4 as a potential therapeutic target for diffuse midline glioma has just been published in Molecular Cell! Check out co-first author @eimearlagan.bsky.social’s overview below.

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Reposted by James Nolan

Evan Healy @evhealy.bsky.social · 14/01/2025

🧵 1/ We’re excited to share that our new paper with @adrianbracken.bsky.social lab is out 🎉 In this study (which began over 10 years ago!), we explore the biology of PRC2 and PRC1 in non-dividing cells. We also explore the effects of PRC2 inhibitor drugs on these cells. Here’s what we found👇

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James Nolan @jamesnolan.bsky.social · 05/12/2024

Looking forward to sharing collaborative work by myself and @dr-chromatin.bsky.social from the labs of @adrianbracken.bsky.social and @conwayer1.bsky.social at #ASH24 in San Diego this week. #hemesky #lymsm please feel free to stop by and share your thoughts.

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Reposted by James Nolan

Nihar Desai MD, DM @nihardesai7.bsky.social · 21/11/2024

🎉📢 Delighted to share our work from Princess Margaret Cancer Centre 🙌🏼 PTCy-based GvHD prophylaxis was associated with an improved GRFS, NRM, and OS 💪🏼 A big shout-out to @haemophage.bsky.social for his mentorship 🙌🏼 doi.org/10.1182/bloo... #MedSky #HemeSky

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Reposted by James Nolan

Evan Healy @evhealy.bsky.social · 20/11/2024

How does PRC1 counteract transcription? See this preview from @adrianbracken.bsky.social and I on an exciting new study from @robklose.bsky.social lab where they show ncPRC1 blocks the early stages of transcription. www.sciencedirect.com/science/arti... @conwayer1.bsky.social for title inspo!

authors.elsevier.com

ScienceDirect.com | Science, health and medical journals, full text articles and books.

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Reposted by James Nolan

Emma M. Groarke @emmamgroarke.bsky.social · 16/11/2024

My colleague @fergutierrezro1 giving an excellent talk at #ESHBMFS2024 on the clinical implications of clonal hematopoiesis in #telomere biology disorders 🧬; dependent on specific mutation with U2AF1, TP53, and chr1+ associated with #MDSsm and #AMLsm.

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