Jacob Hepkema

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/...

0/ Essential reading for anyone training or using sequence-function models trained on genomic sequences! 🚨 In our new preprint, we explore the ways homology within genomes can cause leakage when training sequence-based models and ways to prevent it

Looks like a very useful method for deeper chromatin accessibility analysis!

Enhancer scrambling strategy

We are happy to share our enhancer scramble story, a strategy to create hundreds of stochastic deletions, inversions, and duplications within mammalian gene regulatory regions and associate these new architectures with gene expression levels 🧵
www.biorxiv.org/content/10.1...

This is really cool - quite precise control! I especially like the collision avoidance system (I'm imagining parking beeps with each exclamation mark)

EXTRA-seq: a genome-integrated extended massively parallel reporter assay to quantify enhancer-promoter communication Precise control of gene expression is essential for cellular function, but the mechanisms by which enhancers communicate with promoters to coordinate this process are not fully understood. While seque...

Finally out! We present EXTRA-seq, a new EXTended Reporter Assay to quantify endogenous enhancer-promoter communication at kb scale!
www.biorxiv.org/content/10.1...
A 🧵about what it can do:
#SynBio #DeepLearning #GeneRegulation

Congratulations Cansu!!

DART-Eval: A Comprehensive DNA Language Model Evaluation Benchmark on Regulatory DNA Recent advances in self-supervised models for natural language, vision, and protein sequences have inspired the development of large genomic DNA language models (DNALMs). These models aim to learn gen...

(1/10) Excited to announce our latest work! @arpita-s.bsky.social, @amanpatel100.bsky.social , and I will be presenting DART-Eval, a rigorous suite of evals for DNA Language Models on transcriptional regulatory DNA at #NeurIPS2024. Check it out! arxiv.org/abs/2412.05430

Really cool work!

By definition, enhancers can activate from a distance. But with increased distance between enhancer and promoter, the activation drops. To study this systematically, we build a synthetic locus: www.cell.com/molecular-ce... 1/12

Does my mutation have the same impact as yours? Population genetics 🤠 🥸 🤓 🤡 meets single cell CRISPRi ⚡ ! www.biorxiv.org/content/10.1... Led by Claudia Feng, Oliver Stegle, Britta Velten, @sangerinstitute.bsky.social .