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This has been a huge team effort, and I’d like to thank everyone involved!

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Final model: The neo-CTCF site blocks super-enhancer-mediated activation of SESN3. Reduced SESN3 disrupts the SESN3–GATOR2 interaction, activating mTOR signalling and promoting immune activation.

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So what does this mean for T-cell biology? SESN3 knockout increased mTOR signalling—but only during amino acid starvation. We traced this to an interaction between SESN3 and GATOR2 that is disrupted by tryptophan, linking the genetic effect directly to nutrient sensing.

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But did this rewiring of the non-coding genome actually lead to a downstream effect? We first showed that the CTCF site blocks a T cell-specific super-enhancer from contacting SESN3 as effectively, reducing SESN3 expression.

We then combined MCC with base editing to show that the CTCF site is the key mechanism. Editing heterozygous cells gave 6 distinct outcomes, revealing that the structure only changes when the CTCF site is mutated on the gain-of-function allele.

We then applied the platform to autoimmune genetics in CD4 T cells, nominating target genes for hundreds of loci. Our favourite example was a gene-desert locus with striking effects on nanoscale and long-range chromatin architecture. Here, the disease-associated allele created a new CTCF site.

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We also phased other heterozygous SNPs at each locus to the captured variant. When phased SNPs lay within gene bodies, we used allelic skew in RNA expression to connect enhancer genotype to transcriptional outcomes.

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We can also measure long-range contacts from the reference and alternate alleles separately. This allows us to identify the genes that a variant can control.

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Comparing maternal and paternal alleles provides a sensitive way to detect functional variants. Using ultra-short-range 3C junctions, MCCv resolves the nanoscale architecture of individual alleles, revealing reproducible differences between active/open and inactive/closed chromatin.

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Delighted to see our latest paper out in @natgenet.nature.com ! The brilliant @jhamley98.bsky.social developed MCCv, allowing chromatin architecture to be visualised at base-pair resolution for each allele—a powerful way to identify functional genetic variants. www.nature.com/articles/s41... 🧵

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We then applied the MCCv platform to autoimmune genetics in CD4 T cells, nominating target genes for hundreds of loci. Our favourite was a gene-desert locus with striking effects on nanoscale and long-range chromatin architecture. Here, the disease-associated allele created a new CTCF binding site.

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We can also measure long-range contacts from the reference and alternate alleles separately. This allows us to identify the genes that a variant can control.

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Together, this links a noncoding autoimmune disease variant to altered 3D genome architecture, reduced SESN3 expression, nutrient sensing and autoimmune disease biology. This has been a huge team effort, and I’d like to thank everyone involved!

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SESN3 knockout increased mTOR signalling, but only when cells were exposed to low amino acid levels. We narrowed this signal down to a biochemical interaction between SESN3 and GATOR2 that is disrupted by adding tryptophan, connecting the genetic mechanism to nutrient sensing and mTOR regulation.

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We next investigated how this altered regulation might affect T-cell biology, focusing on the function of SESN3 and its relationship with nutrient sensing and mTOR signalling.

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SESN3 expression is reduced by super-enhancer blocking

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We then applied the MCCv platform to autoimmune genetics in primary human CD4 T cells across hundreds of disease-relevant loci. Our favourite was a gene-desert locus where we found a new mechanism: the disease-associated allele created a new CTCF binding site.

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We can also measure long-range contacts from the reference and alternate alleles separately. This allows us to identify the genes that a variant can control.

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Rob Beagrie @rbeagrie.bsky.social · 19/02/2026

Making use of the base-pair resolution of the method, we plotted 3C junctions from within the enhancer (ultra-short range), defining the nanoscale architecture of individual alleles.

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Reposted by James Davies

New preprint from @anadopico.bsky.social (who I have had the great pleasure of supervising with Tom Milne) and our fantastic collaborators in the @davieslab.bsky.social www.biorxiv.org/content/10.6... #genomics #GeneRegulation #chromatin

A pictographic model of chromatin folding in the nucleus. DNA wrapped around nucleosomes aggregates into nanoscale domains, whilst newly nucleosome depleted DNA that forms after acute degradation of FACT projects from these domains and engages in long-range interactions that can span TAD boundaries

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Reposted by James Davies

Roman Doll @romanmdoll.bsky.social · 20/12/2025

Excited to share that a part of my PhD work is online now on BioRxiv! www.biorxiv.org/content/10.6... We developed a genome editing approach to target the JAK2 V617F mutation and demonstrate its potential to alleviate MPN hallmarks in primary patient cells. Thread 👇

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Reposted by James Davies

Rosana Collepardo @rcollepardo.bsky.social · 05/12/2025

Our Science paper is out! Huge congratulations to @huabin-zhou.bsky.social, Mike Rosen, and the brilliant @janhuemar.bsky.social @juliamaristany.bsky.social and @kieran-russell.bsky.social from our group News: bit.ly/4avnkAr and bit.ly/3XBGVHS Great perspective by @vram142.bsky.social +K Zhang

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James Davies @jojdavies.bsky.social · 02/12/2025

Fascinating paper on a number of levels… Anyone else think that NASA are basically saying that it’s likely that DNA/RNA/protein based life is likely to predate the solar system and arrived on earth on a comet… So there are likely to be DNA based life forms throughout the universe?

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Reposted by James Davies

Ross Chapman @rosschapmanlab.bsky.social · 01/12/2025

New lab preprint! ERCC6L2 disease is a recessive bone marrow failure syndrome caused by mutations in the putative DNA helicase ERCC6L2. Using mouse genetics, biochemistry and AF3 we uncover ERCC6L2-MRI as a KU-regulatory complex stimulating NHEJ at staggered DSBs: www.biorxiv.org/content/10.1...

biorxiv.org

The ERCC6L2-MRI-KU complex coordinates NHEJ at staggered DNA double-strand breaks

ERCC6L2 disease is a recessive bone marrow failure (BMF) syndrome caused by mutations in the SNF2-like putative DNA helicase ERCC6L2. While implicated in DNA replication, double strand break (DSB) rep...

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James Davies @jojdavies.bsky.social · 01/12/2025

Thanks so much for highlighting our images created with @rcollepardo.bsky.social

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Reposted by James Davies

Radcliffe Department of Medicine @rdm.ox.ac.uk · 06/11/2025

Scientists have the most detailed view yet of how DNA folds and functions inside living cells! The breakthrough helps us understand how genetic differences lead to disease and opens up fresh routes for drug discovery 👇 shorturl.at/nQjsx @jojdavies.bsky.social @imm.ox.ac.uk @medsci.ox.ac.uk

shorturl.at

Oxford scientists capture genome’s structure in unprecedented detail

RDM scientists have achieved the most detailed view yet of how DNA folds and functions inside living cells, revealing the physical structures that control when and how genes are switched on.

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Reposted by James Davies

Marieke Oudelaar @mariekeoudelaar.bsky.social · 27/10/2025

Happy to share our latest publication, in which we show that the arrangement of nucleosomes around CTCF sites contributes to higher-order organisation of chromatin into TADs: www.embopress.org/doi/full/10....

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Thanks Elzo! It has been a real pleasure collaborating with you on this.

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The Lister Institute of Preventive Medicine @thelisterinstitute.bsky.social · 05/11/2025

Yes that’s correct - they are due to ligation junctions between the linkers of adjacent nucleosomes which have a fixed distance between them but a variable position with respect to the DNA sequence.

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Reposted by James Davies

Not from Tron or a psychedelic wallpaper. This exquisite pic reveals chromatin at base-pair resolution, captured by #ListerFellow James Davies and collaborators🤩 "For the first time, we can see how the genome's control switches are physically arranged inside cells." @jojdavies.bsky.social

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Finally, we propose a model in which chromatin is self-organising based on histone acetylation and nucleosome depletion. We hypothesise that active cis-regulatory elements may contact one another at or above a layer of acetylated nucleosomes.

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We then collaborated with Lothar Schermelleh to undertake super-resolution microscopy of chromatin acetylation. In keeping with his previous work we find that histone acetylation maps to regions of chromatin that are adjacent to the interchromatin compartment.

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And histone acetylation drive the formation of the nanoscale domains we see in the MCC data. This leads us to conclude that the biophysical properties of chromatin, particularly nucleosome depletion and histone acetylation, drive fine scale structure.

We show that nucleosome depletion....

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In collaboration with Rosana Collepardo-Guevara who has develops a chemically specific molecular dynamic simulation of the physicochemical properties of chromatin, we constructed an MD simulation of the Myc promoter that closely matches the MCC data.

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However, at other sites only the intricate structure of the nucleosome depleted region changes. From this we conclude that nucleosome depletion itself is a major driver of long-range contacts.

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At some sites SOX2 depletion causes complete collapse of the nucleosome depleted region at the enhancer and loss of all contacts.

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In collaboration with Rob Klose and Elzo de Wit, we explored the role of depletion of the mediator complex components (MED14, MED13 and MED1) and transcription factors (SOX2 and NANOG).

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We are able to map specific structures within the nucleosome depleted regions at regulatory elements that are driven by transcription factors.

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Between nucleosome depleted regions we see nanoscale domains, that appear similar to TADs but are approximately 100- to 1000-fold smaller

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