Elphege Nora Lab at UCSF

Cohesin drives chromatin scanning during the RAD51-mediated homology search Cohesin folds genomes into chromatin loops, the roles of which are under debate. We found that double-strand breaks (DSBs) induce de novo formation of chromatin loops in human cells, with the loop bas...

Thrilled to share that my postdoc research is published today in @science.org! We found that DNA repair uses cohesin complexes to build new chromatin loops that guide the homology search and boost accurate repair! 1/n
www.science.org/doi/10.1126/...

10/12
Our model:
🔹 Loop-forming cohesin sets a megabase-scale search radius within the TAD
🔹 Cohesive cohesin forms a local clamp that tethers DNA ends to the sister chromatid
Together, they focus RAD51 sampling and enable accurate repair!

Cohesin guides homology search during DNA repair using loops and sister chromatid linkages Accurate repair of DNA double-strand breaks (DSBs) is essential for genome stability, and defective repair underlies diseases such as cancer. Homologous recombination uses an intact homologous sequenc...

I am happy to share that my postdoctoral work in the @gerlichlab.bsky.social at @imbavienna.bsky.social is finally out 🎉!
Our study reveals how cohesin guides focused and accurate homology search.
Read more 👉 www.science.org/doi/10.1126/...
Follow along for key insights and updates! 🧵

YouTube video by Sciences de la vie - Collège de France L'inactivation du chromosome X (12) - Edith Heard (2024-2025)

(29) PS: here is a link to a public presentation of this work on enhancer biology

m.youtube.com/watch?v=8OdG...

Courtesy @college-de-france.fr

From Postdoc to PI : a limited series from ALBA Network - The Lonely Pipette : helping scientists do better science We had the great honour of producing a podcast for the ALBA-IBRO Diversity Podcast.This podcast series is a unique resource, a guide that will help you to adress the difficult issue of transitioning f...

💥 We’re back with a bang!
After a quiet six months, we’re excited to share our new collaboration : a podcast for @network-alba.bsky.social on navigating the postdoc-to-PI journey.
🎧 Listen to what happened here : thelonelypipette.buzzsprout.com/1356877/epis...

📣 I hereby make my Bluesky debut to announce that our work linking DNA binding affinities and kinetics 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰 and 𝘪𝘯 𝘷𝘪𝘷𝘰 for the human transcription factor KLF1 just got published in Cell! @cp-cell.bsky.social

www.cell.com/cell/fulltex...

Key findings in a thread (1/6):

🧩 What breaks when you remove DNA loop extrusion?
Gastruloids show it: not lineage decisions… but morphogenesis.

That’s our contribution to www.science.org/doi/10.1126/...

Huge thanks to the amazing @karissalhansen.bsky.social + @elphegenoralab.bsky.social for leading this fantastic work 🙌

Enhancer cooperativity can compensate for loss of activity over large genomic distances Thomas, Feng, et al. introduce a synthetic platform that allows the building of complex regulatory landscapes. Integrating the same enhancer at different distances from a promoter uncovered that activ...

Thank you Christa - this must be another manifestation of the process you described for how enhancer cooperativity can compensate for loss of activity over large genomic distances

www.cell.com/molecular-ce...

Great pairing for journal clubs 😆

Synergy between regulatory elements can render cohesin dispensable for distal enhancer function Enhancers are critical genetic elements controlling transcription from promoters, yet how they convey regulatory information across large genomic distances remains unclear. Here, we engineer pluripote...

(28) Some speculations about what this could mean for genome regulation 🧠💭

> 38 supplementary figures in case you'd like more details 🤓
www.science.org/doi/10.1126/...

Revisions required > 20 knockin alleles and >60 4C libraries - kudos @karissalhansen.bsky.social 💪

(27) We could recreate CTCF insulator bypass at the Car2 locus by introducing SRR2

🤯

> How many TAD boundaries throughout the genome get bypassed by enhancers through this synergy mechanism? 👀 👀 👀

Functional maps of a genomic locus reveal confinement of an enhancer by its target gene Genes are often activated by enhancers located at large genomic distances, and the importance of this positioning is poorly understood. By relocating promoter-reporter constructs into thousands of alt...

(26) Car2 does not become completely independent of extrusion though - Sox2 must have other unusual features.

Maybe (an)other element(s) in the locus?
Or the unusual regulatory behavior of the gene body as in @basvansteensellab.bsky.social ?
www.science.org/doi/10.1126/...

🤷‍♂️

(25) Putting SRR2 Car2 makes the locus less reliant on cohesin loop extrusion

> so proximal and distal enhancers seem to synergize in a pretty degenerate way (read: it's not locus-specific, you can mix and match regulatory elements, to some extent)

(24) Using 4C we did not find evidence regulatory element synergy works by maintaining long-range chromosome folding independently of cohesin 😦

It also does not operate LDB1 here ❌

> molecular mechanism of enhancer synergy still to be investigated (get in touch!) 🔍

(23) If you move SRR2 further than ~20kb from the Sox2 promoter, it cannot support cohesin-independent action of the distal enhancer.

~20kb was the cuttof we say at Car2 for cohesin-independent action of enhancers. Makes sense!

(22) Strikingly, you can replace SRR2 with other weak enhancers to restore cohesin-independence at Sox2

> SRR2 is not special
> proximal and distal elements likely generally synergize in a cohesin-independent way

(thank you @chribue.bsky.social for highlighting the Map4k3 E2 enhancer!)

(21) ✨New data in the revised version ✨:

a) is SRR2 special in how it bolsters the action of the distal Soz2 enhancer independently of cohesin?

b) How does it work?

c) can we transplant it to change the cohesin-dependence a locus (e.g. Car2?)

(20) Additional authors on bluesky
@rinishah.bsky.social
@bffswithbiology.bsky.social

(19) This was a heroic effort by graduate student
@karissalhansen.bsky.social with the help of @annieadachi.bsky.social , and many wonderful collaborators in our lab and in
@dewitlab.bsky.social
@gfudenberg.bsky.social
@robertblelloch.bsky.social
groups

(18) How does the SRR2 work to boost the effect of distal enhancers? Condensate biophysics? Unknown looping factors? 🤷

How can we hunt for similar elements across the genome & across cell types? 🧪🧬❓

We would love to know – check out the paper for some discussion.

(17) So it’s not that complicated in the end:

If you rely on an enhancer, you will need cohesin extrusion beyond ~18kb.

UNLESS you have a promoter-proximal regulatory element that can synergize with your distal enhancer – which happens independently of

(16) Why? Quite simply, you have now removed the two redundant axes that support long-range enhancer action at Sox2.

(15) That’s because SRR2 is there to support cohesin-independent regulatory communication:

Delete SRR2 when extrusion is blocked by the CTCF sites, and now they insulate very well.

(14) Others already noticed that distal enhancers can still activates Sox2 even if you put really strong CTCF sites in between.

We see that’s true even for sites that insulate *very well* at the Car2 locus.

Why is CTCF insulation not working well at Sox2?

13) Are there other contexts where the cohesin-independent synergy between SRR2 and distal enhancers is at play?

Yes, when we block extrusion with strong CTCF sites.
🛑🚧🛑

(12) So SRR2 mediates a cohesin-independent mechanism to support the communication of Sox2 with its distal enhancer 100kb away.

For Sox2, this regulatory axis and loop extrusion are redundant: that’s why you need to disable both to see a transcriptional effect.

(10) Wait. How can Sox2 work without extrusion? Its enhancer is 100kb away – that’s very far.

Loooots of detective work later 🕵️‍♀️ the answer is crystal clear: it’s all about an inconspicuous genetic element 3kb downstream of the promotor called SRR2.😲

(9) What is we drive Car2 with a crazy strong enhancer?

Let’s grab the Sox2 super-enhancer, since we know it does not really need cohesin to work at Sox2.

Same cut off: 18kb.

So your host locus, not your enhancer, decides if you need cohesin or not for distal regulation.

(8) By relocating enhancers closer and closer to the Car2 promoter we can render it completely resistant to inhibiting extrusion, although it is normally very dependent on extrusion

The cut off: 18kb. Above that the Car2 enhancers need extrusion to work.

(7) Do enhancers need cohesin to work then?

Some yes (e.g. at the Car2 locus)
Some not really (e.g. everyone’s favorite Sox2)

Why is that?

(6) Back to the gene loci that are dysregulated: why are some but not all genes messed up?

Smit Kadvani and
@gfudenberg.bsky.social
noticed that down-regulated genes lie in enhancer-rich chromosome neighborhoods

That makes sense with the tissue-specific dysregulations.