New paper! How do RNAs "know" where to go inside a cell? We dug into the sequence elements that route RNAs to the right place. It turns out that, in mammals, they're surprisingly massive (>200 nt), multipartite, and wonderfully complicated. 🧵
Emmanuel Cazottes
@manucazottes.bsky.social
Gene regulation, ML and stem cells | Postdoctoral fellow w/ @carldeboer.bsky.social @sbmeubc.bsky.social | PhD w/ @crougeulle.bsky.social @upcite.bsky.social | Roamer of the non-coding genome 🌐 https://emmanuelczt.github.io/
In a new preprint we benchmarked Active learning strategies in order to improve Sequence-to-expression models 🤖🧬 TLDR: AL improves performance on generalization tasks and selects data with high biological relevance! Check out the preprint and 🧵 by co-author @muntakimrafi.bsky.social to know more! 👇
Abdul Muntakim Rafi@muntakimrafi.bsky.social · 2mo ago1/14 Sequence-to-expression (S2E) models keep getting better at reading cis-regulatory logic. But they haven't solved it. On tasks like variant effect prediction they're still far from accurate. Remember, solving cis-regulation is the goal and we're not going to settle for less!
Beautiful new study from @elphegenoralab.bsky.social and Leonid Mirny's lab: Cohesin-bridged encounters mediate enhancer-promoter communication, predicting how enhancer effect scales with genomic distance and - for the first time - how CTCF sites modulate enhancer-promoter communciation! 🧵 below
Elphege Nora Lab at UCSF@elphegenoralab.bsky.social · 3mo agoWhy can't we explain enhancer action despite 2 decades of chromosome conformation technologies? 😬 Our new study spearheaded by Leonid Mirny's group points to a flaw in our assumptions, and to a solution from physical principles By @timothyfoldes.bsky.social 💻& @karissalhansen.bsky.social 🧪 🧵👇
Preprint announcement! It was really fun teaming up with @timothyfoldes.bsky.social and the Mirny lab et al. for this one 🤝
Elphege Nora Lab at UCSF@elphegenoralab.bsky.social · 3mo agoWhy can't we explain enhancer action despite 2 decades of chromosome conformation technologies? 😬 Our new study spearheaded by Leonid Mirny's group points to a flaw in our assumptions, and to a solution from physical principles By @timothyfoldes.bsky.social 💻& @karissalhansen.bsky.social 🧪 🧵👇
Why can't we explain enhancer action despite 2 decades of chromosome conformation technologies? 😬 Our new study spearheaded by Leonid Mirny's group points to a flaw in our assumptions, and to a solution from physical principles By @timothyfoldes.bsky.social 💻& @karissalhansen.bsky.social 🧪 🧵👇
Excited to share our new study on CpG islands (CGIs) regulation by transcription factors (TFs)! CGIs drive most transcription initiation with unclear regulation. We find that chromatin-opening TFs are key players—following a surprisingly simple rule. 🧵 www.biorxiv.org/content/10.6... 1/9
biorxiv.org
Agentic systems are adept at solving well-scoped, verifiable problems in computational biology www.biorxiv.org/content/10.6...
biorxiv.org
We are so excited to see our work out in @nature.com! We present a multi-omic single-cell atlas of 12 organs in human fetal development, explore the enhancer landscape, use deep learning to infer rules of transcription factor activity, and interpret non-coding variants in complex traits: #GeneReg 🧬🖥️
John Greally@greally.bsky.social · 4mo agoThis @anshulkundaje.bsky.social, Kyle Fahr and William Greenleaf paper is finally out, we've been following it for a while in its preprint form, phenomenal work. www.nature.com/articles/s41...
MPRAs are the gold-standard tool for measuring how DNA sequences drive gene expression and prioritizing variant effects. In this preprint we asked: does it matter WHERE you place a variant in an MPRA? Spoiler: yes, and it might lead you to miss disease-causing variants. 1/6 doi.org/10.64898/202...
Position-dependent variant effects reveal importance of context in genomic regulation
Gene expression is governed by the DNA sequence, which is read out through complex interactions between transcription factors (TFs), co-activators, and chromatin. Massively Parallel Reporter Assays (MPRAs) provide a high-throughput framework for functionally characterizing how regulatory DNA sequences impact the expression of a model gene. MPRAs have also proven to be useful for measuring the effects of genetic variation, where each allele is typically tested in the center of ~200 bp of genomic context cloned into the MPRA, but the impact of variant position and local context remains largely unexplored. In this study, we systematically investigate how shifting the position of a variant within an MPRA probe influences its regulatory activity using models that predict expression in MPRAs from DNA sequence. We find that while the direction of variant effects is usually preserved across positions, the magnitude of expression changes can vary substantially depending on where the variant is placed within the construct. This positional bias appears to be largely explained by the strong position-dependent activity of TFs whose binding the variants perturb. In a subset of cases, interactions consistent with cooperativity between TFs also contribute to position-specific effects. ~1% of variants appear to disrupt RNA polymerase III (Pol III) promoters within Alu elements, resulting in position-specificity because both A and B boxes are required for function and exclusion of either motif due to window shifts disrupts the variants' effects. However, we saw little evidence to support the hypothesis that the positional dependence of variant effects resulted from the redundancy of motifs. Overall, our study demonstrates the complexity of cis-regulatory grammar and how it can confound the interpretation of regulatory variants. ### Competing Interest Statement R.T. has filed intellectual property related to MPRA and MPRA models. The other authors declare no competing interests.
biorxiv.org
🔬 X chromosome inactivation: same function, different regulations depending on the species. A study led by @crougeulle.bsky.social with Université Lyon 1 and @embl.org shows that while humans, macaques and marmosets all inactivate one X chromosome, the regulatory mechanisms have evolved differently.
Science in the Keg brings researchers and the #Vancouver community together for a relaxed evening of discovery and conversation on the science of nutrition! No expertise required! Free registration luma.com/3a5g5ktr! In partnership with @scienceinvancouver.com @sbmeubc.bsky.social
Our paper on the evolution of XIST regulatory network in primates is now published in Science Advances! Check out the paper www.science.org/doi/10.1126/... or a digest of our findings emmanuelczt.github.io/posts/2026/0... A short 🧵 of our main findings 👇
Remodeling of XIST regulatory landscape during primate evolution
How gene regulation strategies rapidly evolve across short evolutionary timescales is explored.
science.org
SOOOO MANY GENOMICS MODELSSSS! 😱 Often unclear which is best since they benchmark differently! In this preprint, we introduce GAME, a new framework that utilizes APIs to enable sustainable, uniform model evaluation so we can see which is actually best for each task. doi.org/10.1101/2025...
Finally out! 🥳 Our paper showing how a transposable element (TE) insertion can cause developmental phenotypes is now published @natgenet.nature.com 🧬🦠🐁 Below is a brief description of the major findings. Check the full version of the paper for more details: www.nature.com/articles/s41588-025-02248-5
Enhancer adoption by an LTR retrotransposon generates viral-like particles, causing developmental limb phenotypes - Nature Genetics
Activation of an LTR retrotransposon inserted upstream of the Fgf8 gene produces viral-like particles in the mouse developing limb, triggering apoptosis and causing limb malformation. This phenotype c...
nature.com
We tile through ~300 ultra conserved elements 10bp at a time in 6 taxa (some alive, some extinct), to ask, are they the reason the two skulls below- separated by 160 million years of evolution - are so similar? (image from former PhD student Laura Cook)
The evolutionary foundations of transcriptional regulation in animals www.nature.com/articles/s41... (read free: rdcu.be/evDcA) 🧬🖥️🧪
CAGT was fun! Thanks @carldeboer.bsky.social @sudpinglay.bsky.social and the de Boer lab for organizing! Folks from Seattle, Oregon, and other places. Great community. Arman gave a usual super talk, and Sanchit and Dayag won poster prizes☺️
Postdoc🚨! Come join our HFSP team to uncover how chromatin moves in cells and what this means for genome function! Great opportunity to combine single-cell genomics, live imaging and polymer physics in the unique mammalian retina with @andersshansen.bsky.social, Davide Michieletto & Sandra Tenreiro
Wissenschaftliche*r Mitarbeiter*in/ Postdoc (m/f/d)
Chromatin ist nicht unbeweglich. Es handelt sich um ein hochdynamisches Material, dessen 3D-Struktur zentrale genomische Prozesse – von der Transkription bis zur DNA-Reparatur – steuert. Doch wie verhält sich Chromatin als Material – als Flüssigkeit, Feststoff oder viskoelastisches Gel –, um diese Funktionen in lebenden Zellen auszuführen? Ohne eine Antwort auf diese Frage können wir nicht vollständig verstehen, wie Chromatin bei Krankheiten gestört wird.
mdc-berlin.de
EPIGENETIC HULK READY TO SMASH AGAIN! GET IN LOSERS!
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...
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...
rdcu.be
🧠 Excited to share my main PhD project! We mapped the regulatory rules governing Glioblastoma plasticity using single-cell multi-omics and deep learning. This work is part of a two-paper series with @bayraktarlab.bsky.social @oliverstegle.bsky.social and @moritzmall.bsky.social, Preprint at end🧵👇
Join us on Wednesday next week for two exciting talks on transcription regulation from @kasitc.bsky.social and @davidsuter.bsky.social! You can register at: us06web.zoom.us/webinar/regi...
Very happy to share the peer-reviewed version of our paper in which we study the formation and function of pair-wise and multi-way enhancer-promoter interactions in gene regulation (see thread below): www.nature.com/articles/s41...
CTCF depletion decouples enhancer-mediated gene activation from chromatin hub formation - Nature Structural & Molecular Biology
Karpinska, Zhu and colleagues characterize the structure-function relationship of the genome during cellular differentiation and demonstrate a role for enhancer-promoter interactions in gene regulatio...
nature.com
Marieke Oudelaar@mariekeoudelaar.bsky.social · 2y ago📣 Preprint alert! We have studied the formation of pair-wise and multi-way enhancer-promoter interactions in the #3Dgenome in a lymphoid-to-myeloid transdifferentiation system and learned interesting new things about their function in #GeneRegulation. 1/10 www.biorxiv.org/content/10.1...
💥🥳 At long last, our latest paper is out! Gag proteins of endogenous retroviruses are required for zebrafish development www.pnas.org/doi/10.1073/... Led heroically by Sylvia Chang & @jonowells.bsky.social A study which has changed the way I think of #transposons! No less! 🧵 1/n
Gag proteins encoded by endogenous retroviruses are required for zebrafish development | PNAS
Transposable elements (TEs) make up the bulk of eukaryotic genomes and examples abound of TE-derived sequences repurposed for organismal function. ...
pnas.org
I’m very excited to share our work on the early evolution of animal regulatory genome architecture - the main project of my postdoc, carried out across two wonderful and inspirational labs of @arnausebe.bsky.social and @mamartirenom.bsky.social. www.nature.com/articles/s41...
Chromatin loops are an ancestral hallmark of the animal regulatory genome - Nature
The physical organization of the genome in non-bilaterian animals and their closest unicellular relatives is characterized; comparative analysis shows chromatin looping is a conserved feature of ...
nature.com
🎉 This paper has been a long time and a labour of love (and hardship) for multiple group members, but, finally: we MPRA'ed 25k introgressed variants (Denisovan and Neanderthal) segregating at allele frequencies > 0.15 in humans today to evaluate their potential to regulate gene expression.
bioRxiv Evolutionary Biology@biorxiv-evobio.bsky.social · last yr.Mapping the gene regulatory landscape of archaic hominin introgression in modern Papuans https://www.biorxiv.org/content/10.1101/2025.05.04.652069v1
We quantify the aggregation of >100,000 random protein sequences to train CANYA, a convolution-attention hybrid neural network to predict aggregation from sequence. With @bennibolo.bsky.social www.science.org/doi/10.1126/...
Massive experimental quantification allows interpretable deep learning of protein aggregation
xAI trained on >100,000 random peptides predicts and elucidates primary sequence determinants of aggregation.
science.org
Delighted to share our latest work deciphering the landscape of chromatin accessibility and modeling the DNA sequence syntax rules underlying gene regulation during human fetal development! www.biorxiv.org/content/10.1... Read on for more: 🧵 1/16 #GeneReg 🧬🖥️
Dissecting regulatory syntax in human development with scalable multiomics and deep learning
Transcription factors (TFs) establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility, and regulating gene expre...
biorxiv.org
Our preprint on designing and editing cis-regulatory elements using Ledidi is out! Ledidi turns *any* ML model (or set of models) into a designer of edits to DNA sequences that induce desired characteristics. Preprint: www.biorxiv.org/content/10.1... GitHub: github.com/jmschrei/led...
Programmatic design and editing of cis-regulatory elements
The development of modern genome editing tools has enabled researchers to make such edits with high precision but has left unsolved the problem of designing these edits. As a solution, we propose Ledi...
biorxiv.org