James Davies

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

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

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 👇

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

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?

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...

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...

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

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.

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

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....

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

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.

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

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.

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.

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....

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.

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.

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

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).

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

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

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.

Treatment of a severe vascular disease using a bespoke CRISPR–Cas9 base editor in mice - Nature Biomedical Engineering Engineering a mutant-specific customized base editor precisely corrects a mutation while minimizing bystander edits, leading to substantial phenotypic recovery in mouse models of multisystemic smooth ...

Optimization of a bespoke base editor to treat a severe pediatric vascular disease! 🫀🧬
Our manuscript describes:
1️⃣ Engineering a target-specific BE🧬
2⃣ A *must avoid* bystander edit that occurs with WT SpCas9 BEs! 🙅‍♂️
3⃣ Extension of lifespan after in vivo editing! 🐁✅

www.nature.com/articles/s41...

We’re really excited to see Hangpeng Li present our latest work at the CSH Mechanisms of Eukaryotic Transcription meeting.

In Brief: A new center in San Francisco will offer tailor-made CRISPR therapies to cure children with rare diseases www.nature.com/articles/s41...

CRISPR screening by AAV episome-sequencing (CrAAVe-seq): a scalable cell-type-specific in vivo platform uncovers neuronal essential genes - Nature Neuroscience The authors developed an adeno-associated virus-based high-throughput in vivo CRISPR screening platform for endogenous mouse brain cell types. Using this platform, they define genes and pathways essen...

Excited that the paper presenting our mouse brain in vivo CRISPR screening platform is out today in @natneuro.nature.com!

Great team effort, led by Biswa Ramani and @ivlrose.bsky.social in the Kampmann lab.

www.nature.com/articles/s41...

NIPBL dosage shapes genome folding by tuning the rate of cohesin loop extrusion Cohesin loop extrusion is a major driver of chromosome folding, but how its dynamics are controlled to shape the genome remains elusive. Here we disentangle the contributions of the cohesin cofactors ...

New preprint with @gfudenberg.bsky.social

We find the rate of cohesin loop extrusion in cells is set by NIPBL dosage and tunes many aspects of chromosome folding.

This provides a molecular basis for NIPBL haploinsufficiency in humans. 🧵👇

www.biorxiv.org/content/10.1...

Thrilled that our paper is in print @science.org!!
*Platelets sequester cell free DNA, including free fetal and tumour-derived DNA*
Tweetorial from @l-cmurphy.bsky.social below. Check out the news feature science.org/content/arti... and terrific editorial from Dennis Lo #platelets_in_the_limelight

Comprehensive genome analysis and variant detection at scale using DRAGEN - Nature Biotechnology DRAGEN rapidly identifies diverse types of genetic variants.

DRAGEN rapidly identifies diverse types of genetic variants go.nature.com/4eXQRT1
rdcu.be/ezphs