Timothée Lionnet

Does the noncoding genome actually carry more genetic information than coding seqs? Motivated by this question we mutated every bp in the 10kb MYC locus. Results are even more exciting: Decoding the MYC locus reveals a druggable ultraconserved RNA element www.biorxiv.org/content/10.6...

Pre-assembly of biomolecular condensate seeds drives RSV replication Nature - Viral ribonucleoprotein–viral protein networks form pre-replication centres that nucleate viral factories and drive respiratory syncytial virus replication.

Now out in Nature! We visualize infection of the RNA virus RSV in real-time with single-vRNP resolution to understand how RSV establishes viral factories, biomolecular condensates that act as sites of viral replication. A huge collaborative effort led by Dhanushika Ratnayake!

rdcu.be/e1bBW

Spatial barcoding reveals reaction radii and contact-dependent mechanism of proximity labeling - Nature Chemical Biology A DNA nanoruler platform enables precise measurement of the labeling radii of TurboID and APEX2, uncovering their contact-dependent mechanisms. These findings redefine the enzymology of proximity labe...

Proximity labeling users: check out this study by @zhixingchen2.bsky.social and Peng Zou, which establishes how much contact-dependence vs. diffusion is responsible for biotinylation — tl;dr TurboID has a much smaller effective radius! www.nature.com/articles/s41... 1/2

Long-term evolution of regulatory DNA sequences. Part 1: Simulations on global, biophysically-realistic genotype-phenotype maps Promoters and enhancers are cis-regulatory elements (CREs), DNA sequences that bind transcription factor (TF) proteins to up- or down-regulate target genes. Decades-long efforts yielded TF-DNA interac...

🧬✨ New 2-part review on the evolution of regulatory DNA (enhancers & promoters)! What started as conversations between Gasper Tkačik @istaresearch.bsky.social and our group @embl.org grew into a broader synthesis.

Preprints here:
Part 1: arxiv.org/abs/2601.19681
Part 2: arxiv.org/abs/2601.21480

"NIH will provide a warning when the Common Forms are not used but will not withdraw applications that don’t comply with the use of the Common Forms. We expect the leniency to be in place through May 2026"

grants.nih.gov/faqs#/common...

Dynamic regulation of endogenous transcription factor hubs at single-molecule resolution https://www.biorxiv.org/content/10.64898/2026.01.25.701606v1

Question for the crowd :

Do you have any examples of subunits which have a function independent of the multiprotein complex to which they belong?

I am currently thinking about writing a review (focusing on the Mediator complex and examples of specific subunit functions, such as PMID: 41414671).

The image shows an illustration of the comic book character Doctor Manhattan from the graphic novel Watchmen, depicted sitting on Mars. The text reads: It is 1996, we have a president born in 1946 It is 2006, we have a president born in 1946 It is 2016, we have a president born in 1946 It is 2026, we have a president born in 1946

As someone who spent the last 15 years working with aging brains & dementia, I can't stop thinking about this. It is gerontocracy: leaders who are substantially older than most of the adult population. When did we accept this? The new generations can't show up because the old generations never left.

New preprint on technologies to scale up CRISPR screens.

We use them to map 665,856 pairwise genetic perturbations and outline a path to comprehensive interaction mapping in human cells.

We also introduce an approach for cloning lentiviral libraries with billions of elements.

House Appropriations minibus bill funding NIH is out now.
- $400M increase
- Multiyear funding of new awards capped at 2025 levels.
- No line item for BRAIN Initiative

text here: docs.house.gov/billsthiswee...

Screenshots from Dem summary and Sec 240 (multiyear funding text).

congrats Tim!

AI-assisted protein design to rapidly convert antibody sequences to intrabodies targeting diverse peptides and histone modifications AI-powered pipeline converts antibodies into functional intrabodies, enabling live-cell imaging of peptides and histone marks.

Happy New Year all. I know it's been a draining and difficult year for science in general, but wanted to share some good news: our intrabody paper has now been published in Science Advances with lots of additional data.
www.science.org/doi/10.1126/...

A genetically encoded device for transcriptome storage in mammalian cells Understanding how cells make decisions over time requires the ability to link past molecular states to future phenotypic outcomes. We present TimeVault, a genetically encoded system that records and s...

So cool - someone finally hacked 'the vault'.
www.science.org/doi/10.1126/...

A single cluster of RNA Polymerase II molecules is stably associated with active genes In eukaryotic nuclei, transcription is associated with the clustering of RNA Polymerase II (RNAPII) molecules. The mechanisms underlying cluster formation, their interactions with genes, and their imp...

"RNAPII clusters reflect local accumulations of transcriptionally engaged polymerases and do not form through higher-order mechanisms such as phase separation"

😬

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

by the @mirlab.bsky.social

a close up of a brown surface with a few spots ALT: a close up of a brown surface with a few spots

The appropriations bill that includes NIH is being finalized.

The Senate bill includes a bipartisan amendment from Senators Capito (WV) and Baldwin (WI) limiting multi-year funding of grants.

The House version does not and OMB has issued a veto threat if the House includes such language.

1/3

entering the academic/medical centers are real estate companies in a trench coat era

amazing sunrise here as well!

High-resolution binding data of TFIID and cofactors show promoter-specific differences in vivo TFIID is instrumental in recognizing promoter sequences and initiating transcription, yet a cohesive understanding of how this complex interacts with and functions at different promoter types in vivo ...

The @zeitlingerlab.bsky.social is pleased to announce @sergio-gma91.bsky.social’s preprint “High-resolution binding data of TFIID and cofactors show promoter-specific differences in vivo” (www.biorxiv.org/content/10.6...).

TLDR; TFIID behaves differently depending on promoter type. More below:

The transcription of a single olfactory receptor per neuron is enforced by epigenetic silencing of their enhancers The ability to discriminate thousands of odors in our environment requires each olfactory neuron to express a single olfactory receptor from hundreds of available genes. The biochemical mechanism enfo...

This went under the radar but answers a fundamental question in Epigenetics...

From many hundreds of olfactory receptor genes, each neuron selects expression of only single one (near-randomly). How?

Outstanding work from Mathieu Boulard and colleagues

www.biorxiv.org/content/10.6...

Really encouraging to see siRNA therapies enter the mainstream. A sobering reminder of how long this stuff takes to get to the clinic, though - here's me writing about their promise (and what you'd need to deliver them) in 2005
softmachines.org?p=143

Interphase chromosome conformation is specified by distinct folding programmes inherited through mitotic chromosomes or the cytoplasm - Nature Cell Biology Schooley et al. find that mitotically bookmarked loci drive a transient chromosome folding state during G1 entry that is subsequently modulated by factors inherited through the cytoplasm.

Exciting new paper out! @allanaschooley.bsky.social and Sergey Venev led this project that let to the discovery of two chromosome folding programs: one inherited via mitotic chromosomes and one mitotic inherited through the cytoplasm!

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

1/ 🎄 We got our Christmas present today: "Two distinct chromatin modules regulate proinflammatory gene expression" is now published @natcellbio.nature.com doi.org/10.1038/s415.... Our study introduces a scATAC-seq-based framework for genome-wide analysis of gene regulation features.

As the year ends, let me thank public school teachers who, under difficult circumstances, are doing their best to educate our kids.

If this country is to flourish, we need the best education system in the world. Let’s fight for a nation where teachers are well-paid & respected.

Not that long ago, in vivo mouse enhancer design was a dream. Today, it's a reality! Using transfer deep learning to design de novo synthetic embryonic enhancers active in the heart, limb, and CNS. Great collab with @alex-stark.bsky.social lab! @ucibiosci.bsky.social @impvienna.bsky.social

Predictive design of tissue-specific mammalian enhancers that function in vivo in the mouse embryo Enhancers control tissue-specific gene expression across metazoans. Although deep learning has enabled enhancer prediction and design in mammalian cell lines and invertebrate systems, it remains uncle...

Our preprint "Predictive design of tissue-specific mammalian enhancers that function in vivo in the mouse embryo" is on bioRxiv: www.biorxiv.org/content/10.6... . Amazing collaboration by @shenzhichen1999.bsky.social, Vincent Loubiere (@impvienna.bsky.social,@viennabiocenter.bsky.social),... (1/2)

RNA polymerase II initiation factors show different dynamic behaviour upon induced transcription in live cells Transcription by RNA polymerase II (Pol II) requires the ordered action of general transcription factors (GTFs) forming the pre-initiation complex (PIC). How these events unfold kinetically remains un...

Read our new preprint where we uncover a hierarchy in human PIC assembly and establish a quantitative framework that connects factor exchange kinetics to the regulation of Pol II activity in living human cells. doi: doi.org/10.64898/202...
By A. Oravecz and our collaborators @molinalab.bsky.social

Six (or seven) predictions for AI 2026 from a Generative AI realist 2025 turned out pretty much as I anticipated. What comes next?

“2025 will be known as the year of the peak bubble, and also the moment at which Wall Street began to lose confidence in generative AI... the Oracle craze early in September and what has happened since will in hindsight be seen as the beginning of the end.” garymarcus.substack.com/p/six-or-sev...

I'm working on a new water-dipping objective targeting expansion imaging. Targeting the following specs:

5mm WD
NA 1.0
1.2mm FOV, plan-corrected
8mm EFL ("25x") but this is flexible
well-corrected in visible
minimum mechanical profile

Optics question: is there any reason to make it telecentric?

“A process which led from the amoeba to man appeared to the philosophers to be obviously a progress - though whether the amoeba would agree with this opinion is not known"
- Bertrand Russell, 1976.

Time-lapse video of Vampyrella lateritia eating Spirogyra algae from Science Source/Oliver Skibbe. 🦠

An integrated view of the structure and function of the human 4D nucleome - Nature The 4D Nucleome Project demonstrates the use of genomic assays and computational methods to measure genome folding and then predict genomic structure from DNA sequence, facilitatin...

A major output of the 4D Nucleome project appeared today. This is the joint effort of many scientists working together and (publicly) sharing data and results for several years. We hope this is of interest to many genome biologists!

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