Because dLEM parameters are physically interpretable, we can do something deep learning can't: predict perturbation effects!
Example: WAPL depletion
→ We modified just the detachment rate
→ Successfully predicted emergence of new loops & extended stripes
Example: WAPL depletion
→ We modified just the detachment rate
→ Successfully predicted emergence of new loops & extended stripes
October 21, 2025 at 2:00 PM
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Uma musica que ninguém lembra que existiu, mas que eu amo: www.youtube.com/watch?v=wAPl...
Marshmello & Demi Lovato - OK Not To Be OK (Official Music Video)
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October 12, 2025 at 9:29 PM
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[July 26th, 1980] Advertisement: WAPL 106 FM and JELLO LAGOON present a crazy event: "TAKE A DIVE" at Sound World, Green Bay on July 26. Jump into 675 gallons of green gelatin for prizes like turntables and cassettes.
October 4, 2025 at 4:03 AM
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Gonna put my fucking head through a wapl i cant stand this lady fucking fuck off im sick of her
September 14, 2025 at 1:38 AM
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September 10, 2020
Marshmello & Demi Lovato released "OK Not To Be OK".
www.youtube.com/watch?v=wAPl...
Marshmello & Demi Lovato released "OK Not To Be OK".
www.youtube.com/watch?v=wAPl...
Marshmello & Demi Lovato - OK Not To Be OK (Official Music Video)
YouTube video by Marshmello
www.youtube.com
September 10, 2025 at 12:40 PM
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Postscript: for a long time I was very confused about the PDS5-WAPL depletion expts+sims & how extrusion alters compartments. I was fortunate to eventually stumble across @ranjithpa.bsky.social's preprint www.biorxiv.org/content/10.1... & later this by Chan/Rubinstein www.pnas.org/doi/abs/10.1...
September 3, 2025 at 4:23 PM
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We turned to the possibility of PDS5 competing w/NIPBL for cohesin
PDS5 inhibits cohesin-NIPBL ATPase+binding in vitro & suppresses NIPBL occupancy of cohesin in cells(+ PDS5&WAPL dont affect each others occupancy)
iFRAP shows NIPBL chromatin residence time seems to increase a lot w/ PDS5 depletion
PDS5 inhibits cohesin-NIPBL ATPase+binding in vitro & suppresses NIPBL occupancy of cohesin in cells(+ PDS5&WAPL dont affect each others occupancy)
iFRAP shows NIPBL chromatin residence time seems to increase a lot w/ PDS5 depletion
September 3, 2025 at 4:20 PM
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What about CTCF? PDS5A/B isnt needed to recruit CTCF & it aids cohesin accumulation at CTCF. But PDS5-mediated cohesin accumulation isnt merely due to recruitment to CTCF. PDS5 depletion leads to new accumulation of cohesin elsewhere in “cohesin islands” often at sites of convergent transcription.
September 3, 2025 at 4:20 PM
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Why does PDS5A/B depletion erase compartments as well as WAPL depletion despite differences in residence time? One possibility is that PDS5A/B depletion leads to faster average extrusion speed
September 3, 2025 at 4:20 PM
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How? In polymer sims increasing cohesin residence time can nonmonotonically alter chromatin compartmentalization. Consistently iFRAP showed residence times increase w/ WAPL & PDS5A/B depletion, dramatically so w/ triple depletion (also suggesting partially distinct PDS5 & WAPL-based cohesin release)
September 3, 2025 at 4:20 PM
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As seen previously, PDS5 or WAPL depletion suppress chromatin compartmentalization, but astonishingly, co-depletion of WAPL and PDS5A/B leads to recovery of compartments in near-cis!
September 3, 2025 at 4:20 PM
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In auxin-inducible degron cells, Gordana used Hi-C to observe the loss of extrusion-mediated CTCF-CTCF contacts (corner peaks) with PDS5A/B depletion. Interestingly, while WAPL depletion increases corner peaks, co-depleting PDS5 completely suppresses them
September 3, 2025 at 4:20 PM
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MASMA DREAM WORLD - "PLEASE COME TO ME" OFFICIAL VISUALIZER (Audio)
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September 2, 2025 at 6:40 PM
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29 / and this one illustrates the dramatic differences in loop dynamics after depleting
NIPBL (slow rate, normal lifetime)
WAPL (very high lifetime)
PDS5 (high lifetime, high rate)
NIPBL (slow rate, normal lifetime)
WAPL (very high lifetime)
PDS5 (high lifetime, high rate)
August 19, 2025 at 9:24 PM
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22/ Fear not, this is simply because the rate changes offset each other, but lifetime remains high, just like in the WAPL mutant 🤙
In other words, the net rate of extrusion is set by the respective balance of NIPBL:PDS5 in the cell ⚖️
In other words, the net rate of extrusion is set by the respective balance of NIPBL:PDS5 in the cell ⚖️
August 16, 2025 at 3:03 AM
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21/ The genetics check out with the biophysics:
Co-depleting NIPBL (which reduces extrusion rate) together with PDS5 (which increases extrusion rate AND increase lifetime) made Hi-C look like WAPL inactivation 🤯
Co-depleting NIPBL (which reduces extrusion rate) together with PDS5 (which increases extrusion rate AND increase lifetime) made Hi-C look like WAPL inactivation 🤯
August 16, 2025 at 3:03 AM
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20/ To recap 📓: cohesin cofactors affect loop extrusion dynamics
NIPBL depletion makes loop grow very slowly 🐢
WAPL depletion causes very high lifetime 🕕, loops extend but still need time to grow 🏃
PDS5 depletion causes medium lifetime 🕒, but loops grow very quickly, extending very fast 🐇💨
NIPBL depletion makes loop grow very slowly 🐢
WAPL depletion causes very high lifetime 🕕, loops extend but still need time to grow 🏃
PDS5 depletion causes medium lifetime 🕒, but loops grow very quickly, extending very fast 🐇💨
August 16, 2025 at 3:03 AM
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19/ Timecourse microscopy experiments at the onset of G1 confirmed that PDS5 depletion causes vermicelli to form faster than after WAPL inactivation, supporting that PDS5 accelerate extrusion rate 🚄🚄🚄
August 16, 2025 at 3:03 AM
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18/ Measuring extrusion rates in live cells is not directly possible.
But polymer simulations predicted that faster extrusion after PDS5 loss should create denser cohesin clusters (“vermicelli”) than those known to form after WAPL inactivation.
✔️That’s exactly what microscopy showed!
But polymer simulations predicted that faster extrusion after PDS5 loss should create denser cohesin clusters (“vermicelli”) than those known to form after WAPL inactivation.
✔️That’s exactly what microscopy showed!
August 16, 2025 at 3:03 AM
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17/ ✔️Satisfyingly, by iFRAP @lucagiorgetti.bsky.social indeed saw smaller increase in lifetime after PDS5 vs. WAPL depletion.
August 16, 2025 at 3:03 AM
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16/ Fitting polymer simulations to experiments yielded two testable predictions:
▶️ PDS5 depletion increases lifetime, but not as much as WAPL depletion
▶️ PDS5 depletion increases the rate of extrusion, explaining chromosome hyper-compaction
▶️ PDS5 depletion increases lifetime, but not as much as WAPL depletion
▶️ PDS5 depletion increases the rate of extrusion, explaining chromosome hyper-compaction
August 16, 2025 at 3:03 AM
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15/ Experimentally, compartmentalization is much more suppressed after PDS5 vs. WAPL depletion 💡
August 16, 2025 at 3:03 AM
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13/ Hi-C after PDS5 depletion resembles but is not identical to WAPL depletion: chromosomes become even more compacted.
❓Can our polymer models tell us if it because PDS5 depletion increases cohesin lifetime or extrusion rate?
❓Can our polymer models tell us if it because PDS5 depletion increases cohesin lifetime or extrusion rate?
August 16, 2025 at 3:03 AM
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