Synthetic super-enhancers enable precision viral immunotherapy - Nature Synthetic super-enhancers enable specific delivery of anticancer payloads, achieving tumour elimination after a single dose in a mouse model of aggressive glioblastoma.

Nature research paper: Synthetic super-enhancers enable precision viral immunotherapy

go.nature.com/4soUwPI

ChromSMF preprint is out!🚀
tinyurl.com/ChromSMF

We often piece together chromatin regulation layer by layer from separate assays. But this can be limiting!

In @arnaudkr.bsky.social's lab, we developed a method to directly study multiple layers on the same DNA molecule! 🧬

What does this unlock? ⬇️

The main project of my PhD 🧬🔬 is out: we developed single-cell lentiMPRA, a lentivirus-based method to measure enhancer activity and transcriptomes at single-cell resolution. We then applied sc-lentiMPRA to fully synthetic enhancers 🧩...

🔗 doi.org/10.64898/202...

We wrote a perspective "How to build the regulatory genome: a constructionist guide to the cis-regulatory code", out in Development yesterday. Title says it all. Find it here:

journals.biologists.com/dev/article/...

🚨New preprint! We built a cell-free genomics platform (GATO-seq) to probe transcriptional regulation and discovered a “super pause” sequence that triggers a new Pol II active-site conformation. Huge shout-out to @robertovn.bsky.social for pulling off this monster of a project. tinyurl.com/superpause

Programmatic design and editing of cis-regulatory elements The development of modern genome editing and DNA synthesis has enabled researchers to edit DNA sequences with high precision but has left unsolved the problem of designing these edits. We introduce Le...

After a huge amount of work w/ @alex-stark.bsky.social's group, a new version of our Ledidi preprint is now out!

In an era of AI-designed proteins, the next leap will be controlling when, where, and how much of these proteins are expressed in living cells.

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

First paper from the lab is now online
@natneuro.nature.com !
We mapped injury induced enhancers in the mouse CNS and decoded their sequence architecture. Little 🧵 rdcu.be/eSQi1

Yes, this is where you would work (the round building, not the boat)

We are looking for a postdoc to join our team! If you're interested in translating a cutting edge genomics technology (www.nature.com/articles/s41...) to real-life applications in hematology, this is for you. We offer a unique working environment ON THE BEACH: recruitment.crg.eu/content/jobs...

Generating long deletions across the genome with pooled paired prime editing screens Engineered deletions are a powerful probe for studying genome architecture, function, and regulation. Yet, the lack of effective methods to create them in large numbers and at multi-kilobase scale has...

New 🧬✂️ pre-print! We show that paired prime editing can efficiently generate large deletions — even >1 Mb — with high precision and at scale. We use this to perform the first pooled prime deletion screen across the human genome.

🔗 biorxiv.org/content/10.1...

A short thread (by Juliane Weller)👇

TF-MAPS: fast high-resolution functional and allosteric mapping of DNA-binding proteins Transcription factors (TFs) bind specific DNA sequences to control gene expression. Modulating TF activity is of considerable therapeutic interest but very few TFs have been successfully drugged. TF D...

TF-MAPS: fast high-resolution functional and allosteric mapping of DNA-binding proteins by @XianghuaLi2

Are Transcription Factors really 'undruggable'?

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

De-novo promoters emerge more readily from random DNA than from genomic DNA Promoters are DNA sequences that help to initiate transcription. Point mutations can create de-novo promoters, which can consequently transcribe inactive genes or create novel transcripts. We know lit...

Excited / nervous to share the “magnum opus” of my postdoc in Andreas Wagner’s lab!

"De-novo promoters emerge more readily from random DNA than from genomic DNA"

This project is the accumulation of 4 years of work, and lays the foundation for my future group. In short, we… (1/4)

Activity of most genes is controlled by multiple enhancers, but is there activation coordinated? We leveraged Nanopore to identify a specific set of elements that are simultaneously accessible on the same DNA molecules and are coordinated in their activation. www.biorxiv.org/content/10.1...

Iterative deep learning design of human enhancers exploits condensed sequence grammar to achieve cell-type specificity Yin et al. demonstrate the use of iteratively retrained deep learning models to design synthetic enhancers for progressively higher cell-type specificity. They show the feasibility of model training f...

Interesting piece on automated enhancer design from the Seelig lab: www.cell.com/cell-systems...

Range extender mediates long-distance enhancer activity - Nature The REX element is associated with long-range enhancer–promoter interactions.

Our paper describing the Range Extender element which is required and sufficient for long-range enhancer activation at the Shh locus is now available at @nature.com. Congrats to @gracebower.bsky.social who led the study. Below is a brief summary of the main findings www.nature.com/articles/s41... 1/

A meme-style comic panel with three parts. Left: A stylized enhancer with a mutation, surrounded by colored blocks representing functional motifs, a neural network diagram, chromatin accessibility signal traces, and a sequence motif. Two cartoon mouse embryos below show different LacZ reporter activity patterns. Top right: A hand hovers anxiously between two red buttons labeled “Experiments” and “AI,” with the caption “HOW DO ENHANCERS REALLY WORK?” Bottom right: A sweating superhero wipes his forehead, looking stressed about the difficult choice.

Textbooks: “Enhancers are just a bunch of TFBSs”

But how do they REALLY work?

New paper with many contributors here @berkeleylab.lbl.gov, @anshulkundaje.bsky.social, @anusri.bsky.social

A 🧵 (1/n)

Free access link: rdcu.be/erD22

Conservation of regulatory elements with highly diverged sequences across large evolutionary distances Nature Genetics - Combining functional genomic data from mouse and chicken with a synteny-based strategy identifies positionally conserved cis-regulatory elements in the absence of direct sequence...

How to find Evolutionary Conserved Enhancers in 2025? 🐣-🐭
Check out our paper - fresh off the press!!!
We find widespread functional conservation of enhancers in absence of sequence homology
Including: a bioinformatic tool to map sequence-diverged enhancers!
rdcu.be/enVDN
github.com/tobiaszehnde...

Our latest work now online in Cell:

Rewriting regulatory DNA to dissect and reprogram gene expression

Our new method (Variant-EFFECTS) uses high-throughput prime editing + flow sorting + sequencing to precisely measure effects of noncoding variants on gene expression

Thread 👇

Low overlap of transcription factor DNA binding and regulatory targets - Nature A near-complete survey of transcription factor activities in Saccharomyces cerevisiae reveals that most transcription factors have both activator and repressor activities and limited overlap between t...

To the top of the "to-read" list. Looks like a heroic amount of work from the Hahn lab (large-scale ChEC-seq compendium!) www.nature.com/articles/s41...

DNA-guided transcription factor interactions extend human gene regulatory code - Nature A large-scale analysis of DNA-bound transcription factors (TFs) shows how the presence of DNA markedly affects the landscape of TF interactions, and identifies composite motifs that are recognized by ...

A tour de force study from Taipale&Yin labs. It expands the vocabulary of the Regulatory Code by adding 1131 TF:TF composite motifs that are different from the individual TF motifs. The new composite motifs are enriched in cell-type specific elements and active in vivo
www.nature.com/articles/s41...

Happy to share the latest story from @arnaudkr.bsky.social's lab @embl.org! With @guidobarzaghi.bsky.social, we used Single Molecule Footprinting to quantify how often chromatin is accessible at enhancers after TF and chromatin environment changes! Check our preprint bit.ly/3XQMFxN + thread ⬇️ 1/11

Our new preprint is out! Want to better visualize what your sequence-to-function profile learned? Here is PISA. It also comes in a new BPNet package, which can be used to train many genomics data sets, including MNase-seq data.

CREsted: modeling genomic and synthetic cell type-specific enhancers across tissues and species Sequence-based deep learning models have become the state of the art for the analysis of the genomic regulatory code. Particularly for transcriptional enhancers, deep learning models excel at decipher...

Very proud of two new preprints from the lab:
1) CREsted: to train sequence-to-function deep learning models on scATAC-seq atlases, and use them to decipher enhancer logic and design synthetic enhancers. This has been a wonderful lab-wide collaborative effort. www.biorxiv.org/content/10.1...

Unpicking non-coding genetic variation: Structure-guided modelling holds promise for evaluating how single nucleotide variants affect transcription factor binding. www.biorxiv.org/content/10.1.... @uoe-igc.bsky.social

How does gene regulation shape brain evolution? Our new preprint dives into this question in the context of mammalian cerebellum development! rb.gy/dbcxjz
Led by @ioansarr.bsky.social, @marisepp.bsky.social and @tyamadat.bsky.social, in collaboration with @steinaerts.bsky.social

Just very happy to have our paper out today! A big thanks to all our co-authors, and to Nikolai and @steinaerts.bsky.social for the teamwork over the past years. If you are interested in using our models for cross-species enhancer studies, check out crested.readthedocs.io/en/stable/mo... 🙂

Recently, we've been playing around with using Ledidi to design "affinity catalogs" that exhibit a broad range of activities, rather than just the "most" of a desired activity.

Here are three example catalogs designed for GATA2 binding, chromatin accessibility, and transcription initiation.

Sequence-dependent activity and compartmentalization of foreign DNA in a eukaryotic nucleus In eukaryotes, DNA-associated protein complexes coevolve with genomic sequences to orchestrate chromatin folding. We investigate the relationship between DNA sequence and the spontaneous loading and a...

Our latest work: how can compartmentalization emerge in a eukaryotic genome lacking canonical heterochromatin?
By investigating bacterial genomes put in yeast, we show that the presence or absence of transcription is sufficient!
#chromatin #3Dgenome #generegulation
www.science.org/doi/10.1126/...
👇

Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing Nature Biotechnology - Metabolites can be quantified using a combination of aptamers and DNA barcodes.

Delighted to share our latest paper describing a method to read the levels of hundreds of metabolites or drugs in parallel using DNA sequencing. This method, which we call ‘smol-seq’ (Small MOLecule sequencing), harnesses the power of DNA sequencing for metabolite detection:
rdcu.be/d8xLv (1/6)

Multiplex generation and single-cell analysis of structural variants in mammalian genomes Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) ...

Now out in @science.org w/ @jshendure.bsky.social we present 'Genome-shuffle-seq': a method to shuffle mammalian genomes and characterize the impact of structural variants (SVs) with single-cell resolution in one experiment.

www.science.org/doi/10.1126/...

Randomizing the human genome by engineering recombination between repeat elements We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into re...

We're delighted to share our work on scrambling the human genome using prime editing, repetitive elements, and recombinases in @science.org , led by @jonaskoeppel.bsky.social , @f-raphael.bsky.social , with @proftomellis.bsky.social and George Church.
www.science.org/doi/10.1126/...