Lightnews — Scholar-powered news

Luca Giorgetti lab @FMI

@lucagiorgetti.bsky.social

860 followers 210 following 55 posts

We study transcriptional regulation and chromosome folding using an interdisciplinary approach combining wet- and dry-lab methods. https://giorgettilab.org @fmiscience.bsky.social

giorgettilab.org

Posts Media Videos Starter Packs

Pinned

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · Sep 8

Become our colleague at @fmiscience.bsky.social! The FMI is a very special place to start your lab: a vibrant international institute with world-class research groups and facilities, core funding, fantastic trainees, great colleagues😅, and a collegial culture. Get in touch if you're interested!

FMI science @fmiscience.bsky.social · Sep 8

🚨 We're hiring, please share! The FMI seeks a tenure-track Group Leader (Assistant Prof) in Structural Biology 🔬
Innovative scientists in genome regulation, RNA metabolism, or protein homeostasis—especially using cutting-edge approaches—apply now at www.fmi.ch/education-ca...

12 20

Reposted by Luca Giorgetti lab @FMI

Edda Schulz @eddaschulz.bsky.social · 2d

⚠️ 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

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.

www.nature.com

3 50 100

Reposted by Luca Giorgetti lab @FMI

Francesca Mattiroli @fmattiroli.bsky.social · 10d

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.

Hubrecht Institute @hubrechtinstitute.bsky.social · 12d

Ready to establish your own research group at the Hubrecht Institute for Molecular and Developmental Biology? We’re seeking a tenure-track group leader to develop an innovative research line within our vibrant scientific community. Learn more & apply! https://f.mtr.cool/jncxfqkuds

2 23 16

Reposted by Luca Giorgetti lab @FMI

Francesca Mattiroli @fmattiroli.bsky.social · 17d

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

Vijay Ramani @vram142.bsky.social · 18d

Some (+)ve news to lighten another heavy weekend: our latest preprint (c/o Mattiroli + Ramani labs) is up!
www.biorxiv.org/content/10.1...
A tour-de-force by 1st authors Bruna Eckhardt & @palindromephd.bsky.social, focusing on chromatin replication. RTs welcome; tweetorial in 3,2...(1/n)

The eukaryotic replisome intrinsically generates asymmetric daughter chromatin fibers

DNA replication is molecularly asymmetric, due to distinct mechanisms for lagging and leading strand DNA synthesis. Whether chromatin assembly on newly replicated strands is also asymmetric remains un...

www.biorxiv.org

2 11 37

Reposted by Luca Giorgetti lab @FMI

Jop Kind @jopkind.bsky.social · 21d

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

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...

doi.org

2 15 40

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 12d

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

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 12d

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.

1 1

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 12d

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)

1 1

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 12d

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...

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 12d

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...

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

you guys are too fast :)

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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!

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...

www.biorxiv.org

1 7

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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!

1 1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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...:

1 3

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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...

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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!

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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!

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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?

1 3

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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…

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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!

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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…

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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.

1 3

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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).

1 2

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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.

1 3

Luca Giorgetti lab @FMI @lucagiorgetti.bsky.social · 14d

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!

1 2