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This study wouldn't have been possible without a lot of hard work from all the authors (@ikafetzo.bsky.social is on here) and support from the lab and @uoe-igc.bsky.social colleagues. Author Francesca Taglini also drew this wonderful illustration of our endeavours 🧵 7/9

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In the revised study, we further support this model by analysing DNMT1 degron cells showing loss of methylation is more rapid from heterochromatin than euchromatin. This is consistent with less de novo DNMT activity at heterochromatin 🧵 6/9

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Our data support a model where differential de novo DNMT activity underpins the loss of methylation from heterochromatin in cancer. We suggest heterochromatin becomes hypomethylated because it normally lacks de novo DNMT activity rather than because it is late replicating 🧵 5/9

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We also conducted a DNMT1 rescue experiment finding that this does not revert methylation levels at hypermethylated PMDs. This suggests DNMT1 deletion induced a permanent alteration of chromatin state at these domains 🧵 4/9

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We now demonstrate that these hypermethylated PMDs also display more variable methylation in clinical colorectal tumours consistent with them having a more labile chromatin structure beyond HCT116 cells 🧵 3/9

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Duncan Sproul @sproullab.bsky.social · 26/03/2026

We previously analysed DNMT1 knockout colorectal cancer cells showing that they displayed surprising gains of DNA methylation in H3K9me3 marked partially methylated domains (PMDs). These domains lost H3K9me3, gained H3K36me2 and recruited DNMT3A 🧵 2/9

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Interesting looking study. Seems they are certainly aligned with the neutral-rebel/rebel-rebel #epigenetics camp by invoking chromatin accessibility and TF binding as an epigenetic memory 🤔 (image credit: @zchiang.bsky.social)

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Duncan Sproul @sproullab.bsky.social · 09/02/2026

Found myself sitting between the unlabelled epigenetics/chromatin faint subcloud of Molecular and Cell Biology Researchers (white circle) and Genomics and Bioinformatics Researchers which about sums up my research!

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Duncan Sproul @sproullab.bsky.social · 19/12/2025

Applications for our international #PhD program open until 11th Jan. Come work with us @uoe-igc.bsky.social and @hannahlong.bsky.social to understand DNMT3B in ICF syndrome or with our wonderful colleagues. Details here: institute-genetics-cancer.ed.ac.uk/igc-graduate... #epigenetics Please repost 🙏

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Duncan Sproul @sproullab.bsky.social · 12/12/2025

Last few days to apply for this #PhD project!

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Duncan Sproul @sproullab.bsky.social · 25/11/2025

Project 2: Use human ES cells to determine exactly how DNMT3B mutations cause ICF1 syndrome. Collaboration with @hannahlong.bsky.social: institute-genetics-cancer.ed.ac.uk/igc-graduate... Deadline 11th January 2026 This scheme is flexible if you are interested in other projects. 🧵 3/4

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Duncan Sproul @sproullab.bsky.social · 25/11/2025

Project 1: Use high-throughput mutagenesis and CRISPR screens to understand how gene body methylation impacts transcription. In collaboration with Greg Kudla's group as part of EastBIO program: www.findaphd.com/phds/project... Deadline 15th December 2025 🧵 2/4

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Duncan Sproul @sproullab.bsky.social · 25/11/2025

🚨 Multiple #PhD opportunities for lab or computational applicants. Do you want to understand the molecular basis of #epigenetic dysfunction in human disease? Come work with our group at the fantastic, collaborative @uoe-igc.bsky.social in a beautiful, liveable city. 🧵 1/4 Please repost 🙏

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Duncan Sproul @sproullab.bsky.social · 18/03/2025

For the those in Edinburgh, tonight is the 10th anniversary meeting of the Edinburgh Chromatin, #epigenetics and transcription network (now on bluseky: @edinepigenetics.bsky.social). Do go along to hear some great science. Sad to be missing it due to illness and lack of childcare 😢

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Duncan Sproul @sproullab.bsky.social · 24/02/2025

For those of you in Edinburgh, tree down this morning on the cycle path between Canonmills and Trinity (I think route 13). Have attempted to report to the council. @spokes.org.uk

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We then asked what might cause this relocalisation of DNMT3A. Using ChIP-seq we found that hypermethylated PMDs lost H3K9me3 and gained H3K36me2 suggesting this change in chromatin state enabled DNMT3A recruitment. 🧵 6/8

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Instead we thought the gains in methylation might be caused by another DNMT. We found that DNMT3A but not DNMT3B localised to hypermethylated PMDs suggesting that this was indeed the case. 🧵 5/8

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We therefore wondered why this might have occurred. Despite the links between hypomethylation and late replication, we found that these hypermethylated PMDs remained late replicating using repli-seq. 🧵 4/8

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Duncan Sproul @sproullab.bsky.social · 04/12/2024

We therefore asked what happened to PMDs in DNMT1 KO colorectal cancer cells. We observed a bias towards losses of DNA methylation from PMDs. However, very surprisingly, we also saw that around 10% of H3K9me3-marked PMDs gained methylation in DNMT1 KO cells! 😮😮😮🧵 3/8

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Interested in a #postdoc in Edinburgh working on #interdisciplinary #epigenetics and having this view on your morning commute? Upcoming opportunities to apply for funding below 🧵 1/3. Get in touch if you are interested.

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Duncan Sproul @sproullab.bsky.social · 01/11/2024

Congratulations to Andreanna (now Dr Wright) from the lab on her successful PhD defence yesterday 🥳. Thanks to Kevin Myant and Adele Murrell who were kind enough to act as examiners.

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We propose DNMT3B is recruited to and methylates H3K9me3-marked heterochromatin facilitated by its N-terminal region and HP1. Hypermethylation of heterochromatin in the case of PWWP mutations results from the redistribution of DNMT3B away from H3K36me3. 🧵 7/9

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We show that this interaction with HP1 is direct and that DNMT3B's N-terminal region is necessary and sufficient to interact with HP1. Furthermore, HP1 increases DNMT3B's affinity for H3K9me3 nucleosomes in an EMSA in vitro. 🧵 6/9

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The biggest addition is elaboration of the molecular mechanism responsible for DNMT3B activity at H3K9me3 marked heterochromatin. We show that DNMT3B can pull down HP1 and H3K9me3 from cells in an N-terminus dependent manner. 🧵 5/9

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We've also confirmed that PWWP mutations cause hypermethylation of heterochromatin in an independent cell line. 🧵 4/9

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In the revised version we have utilised catalytic dead PWWP mutant DNMT3B to demonstrate DNMT3B's catalytic activity is required for this hypermethylation. 🧵 3/9

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