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Anders Sejr Hansen @andersshansen.bsky.social · 28/09/2026

Very nice new paper from Paggi, Long, Zhang using physical modeling of RCMC data to reconstruct physical structures of euchromatin at the nucleosome scale: Euchromatin forms condensed domains and E-P interactions largely occur on the surface! www.nature.com/articles/s41...

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Anders Sejr Hansen @andersshansen.bsky.social · 07/09/2026

Enhancer–promoter proximity predicts transcriptional competence but not transcriptional output in the Drosophila brain arxiv.org/pdf/2609.03058

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Anders Sejr Hansen @andersshansen.bsky.social · 03/09/2026

"we found that human sister chromatids are consistently misaligned in the 5′→3′ direction of inherited DNA strands." www.science.org/doi/epdf/10....

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Anders Sejr Hansen @andersshansen.bsky.social · 19/08/2026

we sometimes do bootcamps or workshops over the summer as a lab. Last week we did our microscopy bootcamp: everyone in the lab built a fluorescence microscope :)

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Anders Sejr Hansen @andersshansen.bsky.social · 18/08/2026

Really interesting new paper from Krietenstein and Groth labs showing that FACT depletion has a dramatic effect on microcompartments leading to aberrant microcompartment (AMC) formation through loss of ordered nucleosomes: www.cell.com/molecular-ce...

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Anders Sejr Hansen @andersshansen.bsky.social · 14/08/2026

Nucleosomes and IDRs suppress promiscuous GCN4 binding on minichromosomes www.nature.com/articles/s41...

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(12/12) This has been a wonderful and close collab with @bloodgenes.bsky.social & lab. All credit to Varshini who led all computational work and put it all together and to Chun-Jie who led many experiments with important contributions from all the authors. We'd love feedback and discussion!

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(11/n) Other "3D CREs" have been described incl. beautiful work on Facilitators (Kassouf/Higgs) & Range Extenders (Kvon). A key distinction, Matchmakers promote looping indirectly: Matchmakers mostly don't themselves form loops. Instead they promote crosser loops through targeted cohesin loading.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(10/n) Due to key role of cohesin in E-P regulation www.biorxiv.org/content/10.6... , it may be very important to allocate extrusion near key genes in erythropoiesis, where most of the genome is compacted and silenced and an increasingly specialized gene expression program is adopted.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(9/n) Working in primary human donor-derived cells prevents degron tagging of cohesin. But we perturbed STAG1/2&NIPBL in primary cells and STAG2 in myeloid cells and re-analyzed Blobel lab NIPBL&SMC3 erythroblast data. All perturbations consistent with Matchmaker cohesin-dependence.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(8/n) Matchmakers strengthen during erythropoiesis and correlate with stronger expression of key erythroid genes. KO of key matchmaker-binding TF NFE2 leads to modest reduction in matchmaking and nearby gene expression.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(7/n) Inspired by fountain work, we tested if moderate targeted cohesin loading can explain Matchmakers: stronger crosser loops without visible fountains. Varshini confirmed this w polymer sims. Interestingly, erythropoiesis lead to chromatin compaction, and compaction hides fountains in 3D maps.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(6/n) In contrast to fountains, Matchmakers do not show "fountain pattern" at single loci. Instead, Matchmakers are composed of “crosser loops”. Matchmakers are "altruistic": they help nearby elements form loops largely without themselves engaging as a loop anchor.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(5/n) Prev work identified “orthogonal extrusion stripes” in 3D maps named “plumes” (de Wit), “jets” (Merkenschlager), “fountains” (Mirny, Meister, Ercan et al) and similar aggregate patterns (Vahedi, Xue, et al) Key distinction: Fountains are extrusion stripes at single loci, but not Matchmakers.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(4/n) As expected, pile-up analysis on CTCF sites and promoters show clear insulation. Varshini clustered eryTFs into 4 clusters and saw strong “anti-insulation” at clusters 3+4. We call cluster 3+4 eryTF "MatchMakers" because they match make loops across themselves, without forming loops directly

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(3/n) Recently @bloodgenes.bsky.social lab ID’d key ‘eryTF’ CREs www.science.org/doi/full/10.... When Varshini examined 3D structure around these CREs she discovered “anti-insulation” pattern: Loops that cross these CREs are stronger than loops that don't --> This is opposite of insulation.

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(2/n) Collab with @bloodgenes.bsky.social began with genetic variation: We mapped ultra-high-res 3D genome structure across erythropoiesis using primary human donor derived cells. We can see the E-P loop that FDA-approved cure for Sickle cell disease targets (Fig 1D), but we also see new loops!

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Anders Sejr Hansen @andersshansen.bsky.social · 06/08/2026

(1/n) Excited to share close collab w @bloodgenes.bsky.social led by Varshini & Chun-jie et al How to induce expression of key genes while silencing much of the genome during Erythropoiesis? A: Matchmaker CREs load cohesin near key genes to promote looping & exp: www.biorxiv.org/content/10.6...

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Anders Sejr Hansen @andersshansen.bsky.social · 25/07/2026

We know little about proteins required for long-range compartment 3D interactions, but this @kyleeagen.bsky.social lab preprint shows that NSD3 can make Mb-scale long-range compartment-like interactions: www.biorxiv.org/content/10.6...

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Anders Sejr Hansen @andersshansen.bsky.social · 23/07/2026

Masahiro and I were fortunate to contribute some RCMC analyses to this beautiful paper from Koska and Wysocka that comprehensively dissects the determinants of promoter competition: www.nature.com/articles/s41...

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Anders Sejr Hansen @andersshansen.bsky.social · 14/07/2026

@mileshuseyin.bsky.social and the lab have put together a comprehensive protocol for genome-wide Micro-C and for Region-Capture Micro-C in @natprot.nature.com : www.nature.com/articles/s41... See also the GitHub for a user-friendly end-to-end computational pipeline: github.com/ahansenlab/M...

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Anders Sejr Hansen @andersshansen.bsky.social · 30/06/2026

And thanks so much to Adrian Henggeler and @fenaochs.bsky.social for writing such a thoughtful News&Views: www.nature.com/articles/s41...

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Anders Sejr Hansen @andersshansen.bsky.social · 30/06/2026

The overall conclusion remains the same: Looping probabilities are globally very rare: mean is 1.2% in mESCs and 2.2-2.8% in 4 human cell lines using Micro-C data from www.biorxiv.org/content/10.1... Consistent with E-P loops forming through transient contact: www.biorxiv.org/content/10.6...

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Anders Sejr Hansen @andersshansen.bsky.social · 30/06/2026

We have generated a "mESC mega merge" Micro-C dataset with 54 Billion (!) unique ligations. This map is freely available on GEO. We have also annotated 65,929 consensus loops in mESCs (CTCF, E, P, other) available as a table. The 54B Micro-C map approaches RCMC-resolution genome-wide!

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Anders Sejr Hansen @andersshansen.bsky.social · 30/06/2026

We use BILD-quantified live-cell imaging data to calibrate Micro-C to get absolute quantification (e.g. this loop is looped 5% of the time). We now have 5 calibration points instead of 3, increasing robustness. The synTAD datapoint is the 339CECP cell line from www.biorxiv.org/content/10.6...

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Anders Sejr Hansen @andersshansen.bsky.social · 30/06/2026

Excited to see James' Genome-wide Absolute Quantification of Looping paper out in @natsmb.nature.com : www.nature.com/articles/s41... This has been in collaboration with @lucagiorgetti.bsky.social @leonidmirny.bsky.social @zechnerlab.bsky.social labs. Brief thread below on some key updates

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Anders Sejr Hansen @andersshansen.bsky.social · 29/06/2026

Very interesting new preprint from @jengreitz.bsky.social lab arguing that rather than there being significant enhancer-promoter compatibility, promoters simply differ in their enhancer responsiveness. If promoters are responsive, they respond to all enhancers. www.biorxiv.org/content/10.6...

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(15/n) This has been a very close tri-lab collab with @leonidmirny.bsky.social @zechnerlab.bsky.social All credit to - Harvey led experiments and many analyses and LSTM ML - Henrik led inference and developed VEPI - Jack developed Fyrtarn, lattice-processing pipeline - And rest of team!

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(14/n) LIMITATIONS - We studied n=1 E-P pair --> generality is TBD - CRE-rich many E and many P regions may behave differently - Each of 5 estimates has limitations: ~25-42 nm contacts that last ~10-20 sec is our best estimate, but there is uncertainty - Same for 0.3-1 sec Time Gate - Others too.

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(13/n) Our data points to time gating - E-P contacts too brief (<0.3-1sec) appear to be txn unproductive --> this is likely important for E-P selectivity See also cited work from @lucagiorgetti.bsky.social @elphegenoralab.bsky.social @leonidmirny.bsky.social Dan Larson and others in this area!

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(12/n) t(E-P) ~ 10-20 sec Discussion - E-P contacts are transient (~10-20 sec) but still stabilized above and beyond random diffusive contacts - Consistently, we see E-P dots in RCMC even without CTCFs. - t(E-P) matches residence time of many TFs and general transcriptional machinery

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(11/n) R(E-P) ~ 25-42 nm Discussion - Isotropic action-at-a-distance is difficult to reconcile with E-P selectivity due to volume density of Es+Ps in nucleus. - Direct E-P bridging by txn complexes consistent with biochemistry - But we studied <2kb E, long super-enhancers may behave very differently

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(10/n) Integrating all 5 estimates: - R(E-P) ~ 25-42 nm - t(E-P) ~ 10-20 sec - Time Gate ~ 0.3-1 sec - All point to transient contact mechanism for E-P interactions explaining why they are easy to miss. - W. @voslab.org did structural modeling --> 25-42 nm consistent w. e.g. Mediator-dimerization

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(9/n) ESTIMATE 5 - Perturbations - Cohesin depletion --> near-complete loss of txn - Add insulating CTCF sites --> 90-97% drop in transcription - Polymer sims can only explain if R(E-P)~36 nm and by adding Time Gate: E-P events <0.3-1sec get filtered out and are transcriptionally unproductive.

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(8/n) ESTIMATE 4 - Can a minimal mechanistic model explain the data? - VEPI: Variational E-P inference fully parameterizes mechanistic model - Captures cross-correlation between E-P contact and MS2 bursts - Estimates t(E-P) < 20 sec consistent with transient contact.

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(7/n) ESTIMATE 3 - Does E-P proximity precede transcriptional bursts? - Train LSTM ML model on live-cell E-P+MS2 trajectories - E-P proximity predicts bursts - E-P proximity events last ~15 sec t(E-P) - E-P events match co-localization control --> R(E-P) ~ contact to 30 nm

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(6/n) ESTIMATE 2 - Adding CTCF sites to E and P of 339kb E-P pair increases expression 20x. - But it only mildly decreases E-P 3D distance from median 246 nm to 167 nm. - Can only explain this if R(E-P) is very small, we estimate ~29 nm.

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(5/n) ESTIMATE 1: - Expression scales linearly with RCMC-measured E-P loop strength - Linearity only if R(RCMC) [RCMC capture radius] equals R(E-P) [func E-P interaction radius] - Thus, R(E-P) ~ R(RCMC) ~ 25-42 nm

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(4/n) Next we took 5 complementary approaches to estimate - R(E-P): how close do E and P need to get to activate transcription - t(E-P): how long do E-P interactions last Each of 5 approaches has pros/cons, but they all converge to transient contact with remarkable consistency.

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(3/n) We engineering a synthetic 339 kb E-P pair in 'vacant' region - Vary E-P dist - +/- CTCF at E and P - See nice dot in RCMC maps - Can track E-P 3D distance and nascent RNA from 2Hz to 6+ hours using Super-Res Live Cell Imaging - Txn strictly dependent on E. - New DNA fluor label: synBsr1 (!)

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(2/n) E-P models? Classical model is stable contact, but recent work has pointed to Es activating Ps across >200 nm distances, seemingly ruling out contact. At the same time, transient contact is at the edge of our detection abilities (SI Note 1) Therefore, we took a synthetic biology approach.

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Anders Sejr Hansen @andersshansen.bsky.social · 22/06/2026

(1/n) Very excited to share tri-lab collab (Mirny & Zechner) led by Harvey, Henrik & Jack: Q: How do enhancers & promoters interact in space (contact vs. action-at-a-distance) and time (stable vs. transient)? A: Transient E-P contact (~25-42 nm lasting ~10-20 sec): www.biorxiv.org/content/10.6...

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Anders Sejr Hansen @andersshansen.bsky.social · 05/05/2026

(6/n) All credit to @matteomazzocca.bsky.social @domenicnarducci.bsky.social Simon Grosse-Holz who led the project. It was a privilege to work with Jessica Matthias & Karsten Bahlmann @abberior.rocks - MINFLUX is revolutionary and @abberior.rocks has really done an amazing job commercializing it.

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Anders Sejr Hansen @andersshansen.bsky.social · 05/05/2026

(5/n) we put together a new table with our best estimates of search times between pairs of loci. Numbers do depend on assumptions (see SI Table S3), but search times are much faster than we typically think. At the scale of few hundred kb/nm, frequent contact is both very fast and inevitable.

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Anders Sejr Hansen @andersshansen.bsky.social · 05/05/2026

(3/n) We expanded our studies from 2 to 5 cell lines during revisions. Surprisingly, 2 distinct behaviors: U2OS, RPE cells show straight power law MSD with a~0.3 across all time scales. mESCs, RH30 cells do not show power law behavior at all, but steepen over time. Dynamics-->cell specific

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Anders Sejr Hansen @andersshansen.bsky.social · 05/05/2026

(2/n) Simple Q: how does chromatin move? Answer depends on MSD subdiffusion exponent - increasing E-P separation 10x increases the search time 300-fold (if a=0.8) but 10,000,000-fold (if a=0.2). Using MINFLUX, we could track chromatin dynamics across 7 orders of magnitude for the first time.

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Anders Sejr Hansen @andersshansen.bsky.social · 05/05/2026

(1/n) Super excited to share that our preprint is out today in @natsmb.nature.com with a new name "Integrated MINFLUX tracking reveals two distinct chromatin dynamics classes across cell types" and more than 2x more data: www.nature.com/articles/s41... See also MIT News news.mit.edu/2026/how-chr...

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Anders Sejr Hansen @andersshansen.bsky.social · 13/04/2026

See also the concordant and related papers from @tessapopay.bsky.social @jesserdixon.bsky.social www.nature.com/articles/s41... UkJin Lee @efapostolou29.bsky.social www.nature.com/articles/s41... @karissalhansen.bsky.social @elphegenoralab.bsky.social www.science.org/doi/epdf/10....

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Anders Sejr Hansen @andersshansen.bsky.social · 13/04/2026

Harvey Yang and I were fortunate to contribute polymer simulations to this paper from @nicholas-aboreden.bsky.social Zhao... Zhang, Blobel showing that most CRE loops can form de novo after mitosis without loop extrusion www.nature.com/articles/s41...

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Anders Sejr Hansen @andersshansen.bsky.social · 22/03/2026

Kinetic proofreading as a mechanism for transcriptional specificity: www.biorxiv.org/content/10.6... Very nice follow up to their review from last year genesdev.cshlp.org/content/39/1... Non-equilibrium models may be key to understanding specificity in transcriptional regulation!

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