Luca Giorgetti lab @FMI

Enhancer-promoter compatibility is mediated by the promoter-proximal region Gene promoters induce transcription in response to distal enhancers. How enhancers specifically activate their target promoter while bypassing other promoters remains unclear. Here, we find that the p...

What is a promoter? And how does it work?

We very happy to share our latest work trying to understand enhancer-promoter compatibility.
I am very excited about the results of @blanka-majchrzycka.bsky.social, which changed the way I think about promoters

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

Characterization of induced cohesin loop extrusion trajectories in living cells Nature Genetics - This study introduces a system called TArgeted Cohesin Loader (TACL) that recruits cohesin complexes at defined genomic regions and induces loop extrusion events in living cells,...

The TArgeted Cohesin Loader (TACL) paper was just published. Happy that we were able to contribute to this really exciting project!

If you want to learn how targeting cohesin to defined loci in the genome affects the local chromatin environment and transcription, look no further!

rdcu.be/eLiT5

We are recuiting two new Associate Professors here in Oxford Biochemistry. Come join us! Reach out to me if you have any questions. Please repost! tinyurl.com/mr3m7bd3

Epigenetics and Gene Regulation in Health and Disease: Linking Basic Mechanisms with Therapeutic Opportunities | Keystone Symposia Join us at the Keystone Symposia on Epigenetics and Gene Regulation in Health and Disease: Linking Basic Mechanisms with Therapeutic Opportunities, March 2026, in Geneva, with field leaders!

Come join us in Geneva for everything epigenetics and gene regulation. It will be a great meeting! Please repost!
www.keystonesymposia.org/conferences/...

Reporter CRISPR screens decipher cis-regulatory and trans-regulatory principles at the Xist locus - Nature Structural & Molecular Biology Here Schwämmle et al. develop CRISPR reporter screens to map transcription-factor-regulatory element interactions at the Xist locus, revealing a two-step mechanism integrating developmental and X-dosage signals to initiate X-chromosome inactivation.

⚠️ Paper alert: Using a novel CRISPR screening approach, we mapped the entire regulatory network controlling Xist—key for X-chromosome inactivation.
👉 We discover how sex and development signals are decoded at a single gene locus.
www.nature.com/articles/s41...
👇 Bluetorial

Join us at the Hubrecht Institute in Utrecht to start your research group! Fantastic scientific environment, strong support, and nice colleagues :) Apply and please share broadly in your network.

The latest work from ours and @vram142.bsky.social lab is out! True teamwork to visualize nascent chromatin with strand resolution, using a fully reconstituted system. Very proud of superstar-PhD student Bruna, and @palindromephd.bsky.social. Learning so much from Vijay’s amazing technologies! RT

MeCP2 binding and genome–lamina reorganization precede long gene activation during mouse corticogenesis During corticogenesis, neural gene expression is tightly coordinated by chromatin and epigenetic changes, whose misregulation can lead to neurodevelopmental disorders[1][1]–[4][2]. The role of spatial...

1/ 🧵 I am excited to share a new preprint from our group:
Single-cell Dam&T-seq during mouse corticogenesis reveals how genome–lamina interactions regulate long neuronal genes.
doi.org/10.1101/2025...
#Neurodevelopment #Epigenetics @hubrechtinstitute.bsky.social @oncodeinstitute.bsky.social

Unfortunately we don't have any data or models to answer your question. If nuclear shape changes affect levels of cofactors that determine extrusion rates (NIPBL,PDS5A/B) this could in principle affect extrusion velocity, but I can't personally point you to any data that support this scenario

The 'encounter radius' is an arbitrary physical range, which we vary systematically - and show that its particular choice doesn't affect any of the conclusions.

As you will see in the manuscript, the only condition for two loci to be 'caught' in an extrusion-driven encounter is that cohesin starts extruding approx. midway between their genomic positions (plus of course that their genomic distance is not much larger than cohesin's processivity)

Thanks for the kind words Anders - indeed this is a very much overlooked issue that also affects interpretation of DNA FISH data. Even small amounts of error make determination of 'interactions' unreliable, as your lab also pointed out earlier e.g. in www.sciencedirect.com/science/arti...

We do not impose any specific range, but rather compute (or measure) any events where the two loci spend time within an arbitrary encounter range (R_e in the manuscript), either mediated by random fluctuations or by loop extrusion...

you guys are too fast :)

Loop extrusion creates rare, long-lived encounters underlying enhancer-promoter communication Enhancers regulate transcription from distal genomic positions, but how their spatial encounters with promoters drive activation remains unclear. Using polymer simulations and high-resolution live-cel...

19/ Read about this and much more in our preprint: www.biorxiv.org/content/10.1... Big shoutout to @laureplantard.bsky.social and Laurent Gelman from the @fmiscience.bsky.social facility for imaging & advanced microscopy!

18/ At large genomic distance, long encounters (=the important ones) are only due to loop extrusion; but at short genomic distance they can also be due to random collisions. This is why enhancers are no sensitive to loss of extrusion when they are close, but sensitive when they are far!

17/ ... and nicely predicts @elphegenoralab.bsky.social @karissalhansen.bsky.social's data at the Car2 locus www.biorxiv.org/content/10.1..., using changes in cohesin occupancy and extrusion velocity measured with @gfudenberg.bsky.social in www.biorxiv.org/content/10.1...:

16/ Finally, this simple model also predicts and explains why, at least within simple genomic locations devoid of further confounding effects, depletion of cohesin or its loading and elongation factor NIPBL affects enhancer function at large, but nor short genomic distance...

15/ This happens because by selecting longer and longer encounters, one selects more and more loop-extrusion-driven events, the probability of which is exponential as a function of genomic distance!

14/ This simple model also predicts that transcription levels should decrease exponentially as a function of genomic distance between an enhancer and promoter, exactly as we verified using data from our previous work!

13/ Strikingly, this simple hypothesis predicts that: 1) average transcription levels should increase nonlinearly as a function of enhancer-promoter contact probabilities, as we and others previously observed: www.nature.com/articles/s41... and also work from e.g. Boettiger, de Laat, Wysocka labs

12/...so the probability that such events result in transcription should thus increase when increasing the time that an enhancer and promoter spend in physical proximity. We thus asked: What if only encounters whose duration exceeds an arbitrary cutoff time are productive for transcription?

11/ But why do we care about these longer-lived encounters? Because -although we don’t know exactly what happens there molecularly- it is likely that regulatory processes at an enhancer-promoter interface take some time to occur, and require multiple proteins to be present at the same time…

10/ …and managed to film cells in 3D every 2s with an error in the xy plan of only ~30nm, many times better than our previous measurements! With this in hand, @nessim and @mattia were able to clearly distinguish the appearance of long-lived encounters exclusively in the presence of cohesin!

9/To achieve the spatial and temporal resolutions needed to distinguish between extrusion-driven encounters and random collisions, we introduced a number of improvements in our oblique-illumination microscope setup including efficient sCMOS cameras, optimized laser lines and dichroic / filter sets…

8/We then asked if we could detect extrusion-driven encounters in living cells. We resorted to a cell line previously established in the lab by @piamach.bsky.social, allowing to measure the distance between two operator arrays separated by 150kb in cells mESC where RAD21 can be inducibly degraded.

7/ NB: these loop extrusion-driven, long-lived encounters are longer than random collisions (up to tens of seconds vs. few seconds at most) but are much shorter than CTCF-anchored loops (10-30 sec).

6/ We showed that these encounters only arise when cohesin loads approximately midway between two loci, extrudes them into the encounter radius, and pushes them out after some time.

5/Mattia also discovered that loop extrusion creates a new class of encounters which are extremely rare, but last substantially longer than random polymer collisions. The duration of such encounters depends explicitly on the velocity of extrusion, and it thus a signature of active extrusion!

4/ @mattiaubertini.bsky.social simulated polymer models with and without loop extrusion. He found that loop extrusion reduces the time between consecutive encounters; however this is only because extruded loops make the polymer more compact – not because of the extrusion process itself!