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Posts by Emmanuel Cazottes

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 🧬🖥️

1 week ago 36 20 1 0
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.

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...

1 month ago 13 7 1 2
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Remodeling of XIST regulatory landscape during primate evolution How gene regulation strategies rapidly evolve across short evolutionary timescales is explored.

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

1 month ago 4 2 0 0
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🔬 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.

1 month ago 6 3 1 0
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In partnership with @scienceinvancouver.com @sbmeubc.bsky.social

1 month ago 0 1 0 0

Many thanks to the people who collaborated with us on this study! @charbel-alfeghaly.bsky.social @ireneaksoy.bsky.social Cloé Rognard @crougeulle.bsky.social @agneseloda.bsky.social @rougeulle-lab.bsky.social Anouk Necsulea @heardlab.bsky.social Pierre Savatier, Laura Villacorta, Michael Dong

2 months ago 1 0 1 0

The takeaway: regulatory elements can acquire function before becoming evolutionarily essential. They're complexity waiting to matter !

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Using chromatin profiling and CRISPR, we identified enhancers, chromatin boundaries, and long non-coding RNAs controlling XIST, some conserved, others species-specific. The surprise: when we scanned these functional sequences for signatures of natural selection, most are evolving neutrally.

2 months ago 1 0 1 0
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We often assume that if a DNA sequence does something functional, evolution must have preserved it. Our new study challenges this idea by investigated how the regulatory network of XIST, a gene essential for mammalian development, has evolved across marmosets, macaques, and humans.

2 months ago 0 0 1 0
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Remodeling of XIST regulatory landscape during primate evolution How gene regulation strategies rapidly evolve across short evolutionary timescales is explored.

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 👇

2 months ago 35 14 1 0

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...

9 months ago 20 9 1 1
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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...

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

9 months ago 294 127 15 10
Black and white photos of a thylacine (now extinct) and a grey wolf, in the same pose, looking pretty similar!

Black and white photos of a thylacine (now extinct) and a grey wolf, in the same pose, looking pretty similar!

Lateral adult skull of the c. thylacine and d. wolf. Ventral adult cranium of the e. thylacine and f. wolf. They also look pretty similar!

Lateral adult skull of the c. thylacine and d. wolf. Ventral adult cranium of the e. thylacine and f. wolf. They also look pretty similar!

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)

9 months ago 4 2 1 0
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The evolutionary foundations of transcriptional regulation in animals www.nature.com/articles/s41... (read free: rdcu.be/evDcA) 🧬🖥️🧪

9 months ago 19 16 0 0
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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☺️

10 months ago 8 3 0 0
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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.

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

10 months ago 29 26 1 4
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EPIGENETIC HULK READY TO SMASH AGAIN! GET IN LOSERS!

10 months ago 166 50 11 10
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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...

10 months ago 247 111 7 9
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🧠 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🧵👇

11 months ago 78 29 1 6
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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...

11 months ago 17 10 0 3

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...

11 months ago 103 32 3 3
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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. ...

💥🥳 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

11 months ago 259 108 14 21
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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 ...

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...

11 months ago 268 115 13 12

🎉 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.

11 months ago 83 29 5 0
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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.

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/...

11 months ago 77 29 1 2
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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...

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 🧬🖥️

11 months ago 129 60 2 4
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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...

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...

11 months ago 115 37 2 3
MPRAbase a Massively Parallel Reporter Assay database An international, peer-reviewed genome sciences journal featuring outstanding original research that offers novel insights into the biology of all organisms

One of the toughest parts of the field of massively parallel reporter assays to measure >~thousands of elements is that there are hundreds of pubs using them, but no central repo to easily locate the results....until now! Great collab w/ Jingjing Zhao, Ilias G-S, and @nadavahituv.bsky.social!!

1 year ago 24 9 0 0

Vidéos of the symposium are now available online @collegedefrance.bsky.social Just click and enjoy!🙏🏼🤘

1 year ago 14 5 0 0

I am elated to share that our manuscript describing Variant-EFFECTS, a high-throughput technology we developed to precisely and quantitatively measure the effects of CRISPR-mediated edits on gene expression, is now published at @cellpress.bsky.social: authors.elsevier.com/c/1kxgiL7PXu...

1 year ago 96 35 4 4