Elphege Nora Lab at UCSF
@elphegenoralab.bsky.social
Our laboratory seeks to understand how chromosome structure relates to genome functions
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 😆
www.cell.com/molecular-ce...
Great pairing for journal clubs 😆
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...
www.cell.com
November 27, 2025 at 10:05 PM
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 😆
www.cell.com/molecular-ce...
Great pairing for journal clubs 😆
(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 💪
> 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 💪
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...
www.science.org
November 27, 2025 at 9:59 PM
(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 💪
> 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? 👀 👀 👀
🤯
> How many TAD boundaries throughout the genome get bypassed by enhancers through this synergy mechanism? 👀 👀 👀
November 27, 2025 at 9:59 PM
(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? 👀 👀 👀
🤯
> How many TAD boundaries throughout the genome get bypassed by enhancers through this synergy mechanism? 👀 👀 👀
(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/...
🤷♂️
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/...
🤷♂️
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...
www.science.org
November 27, 2025 at 9:59 PM
(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/...
🤷♂️
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)
> 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)
November 27, 2025 at 9:59 PM
(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)
> 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!) 🔍
It also does not operate LDB1 here ❌
> molecular mechanism of enhancer synergy still to be investigated (get in touch!) 🔍
November 27, 2025 at 9:59 PM
(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!) 🔍
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!
~20kb was the cuttof we say at Car2 for cohesin-independent action of enhancers. Makes sense!
November 27, 2025 at 9:59 PM
(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!
~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!)
> 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!)
November 27, 2025 at 9:59 PM
(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!)
> 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?)
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?)
November 27, 2025 at 9:59 PM
(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?)
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?)
November 27, 2025 at 9:59 PM
(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
@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
November 27, 2025 at 9:59 PM
(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
@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.
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.
November 27, 2025 at 9:59 PM
(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.
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
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
November 27, 2025 at 9:59 PM
(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
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.
November 27, 2025 at 9:59 PM
(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.
Delete SRR2 when extrusion is blocked by the CTCF sites, and now they insulate very well.
November 27, 2025 at 9:59 PM
(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.
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?
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?
November 27, 2025 at 9:59 PM
(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?
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.
🛑🚧🛑
Yes, when we block extrusion with strong CTCF sites.
🛑🚧🛑
November 27, 2025 at 9:59 PM
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.
🛑🚧🛑
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.
For Sox2, this regulatory axis and loop extrusion are redundant: that’s why you need to disable both to see a transcriptional effect.
November 27, 2025 at 9:59 PM
(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.
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.😲
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.😲
November 27, 2025 at 9:59 PM
(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.😲
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.
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.
November 27, 2025 at 9:59 PM
(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.
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.
The cut off: 18kb. Above that the Car2 enhancers need extrusion to work.
November 27, 2025 at 9:59 PM
(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.
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?
Some yes (e.g. at the Car2 locus)
Some not really (e.g. everyone’s favorite Sox2)
Why is that?
November 27, 2025 at 9:59 PM
(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?
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.
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.
November 27, 2025 at 9:59 PM
(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.
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.
(5) But can embryonic cell types properly emerge even when loop extrusion is prevented?
Unambiguous gastruloid experiments by
@bracciolilab.bsky.social
in
@dewitlab.bsky.social
: YES, they clearly can.
Even though morphogenesis, which is normally very stereotypical, is pretty screwed up.
Unambiguous gastruloid experiments by
@bracciolilab.bsky.social
in
@dewitlab.bsky.social
: YES, they clearly can.
Even though morphogenesis, which is normally very stereotypical, is pretty screwed up.
November 27, 2025 at 9:59 PM
(5) But can embryonic cell types properly emerge even when loop extrusion is prevented?
Unambiguous gastruloid experiments by
@bracciolilab.bsky.social
in
@dewitlab.bsky.social
: YES, they clearly can.
Even though morphogenesis, which is normally very stereotypical, is pretty screwed up.
Unambiguous gastruloid experiments by
@bracciolilab.bsky.social
in
@dewitlab.bsky.social
: YES, they clearly can.
Even though morphogenesis, which is normally very stereotypical, is pretty screwed up.
(4) What about inhibiting loop extrusion as cells are differentiating?
Lo(ooo)ts of experiments later:
transcriptional dynamics are largely preserved.
Lo(ooo)ts of experiments later:
transcriptional dynamics are largely preserved.
November 27, 2025 at 9:59 PM
(4) What about inhibiting loop extrusion as cells are differentiating?
Lo(ooo)ts of experiments later:
transcriptional dynamics are largely preserved.
Lo(ooo)ts of experiments later:
transcriptional dynamics are largely preserved.