Will Chen

Thrilled to share my freshly "baked" Baker lab paper. We took a bottom-up approach to designing transcriptional regulators. Instead of relying on natural activation domains, we designed compact proteins that recruit specific cofactors. Activators for now, repressors to come!

I would like to thank David @uwproteindesign.bsky.social for his support and guidance. and @rjiao.bsky.social @kinasekid.bsky.social @cjamesglasscock.bsky.social and other bs-free authors for their help and discussions.

Here is the link for the paper www.biorxiv.org/content/10.6...

biorxiv.orgbiorxiv.org

Our compact binders (~65–85 aa) also proved to be potent CRISPRa effectors, outperforming VPR at several endogenous loci. A combination of these binders further boosts transcription activity.

We hope this framework will open new opportunities to dissect and control both gene activation and silencing with precision, and, more ambitiously, program cell states and functions.

How can weak TAD–cofactor interactions drive strong gene activation? Kinetic simulations suggest that two TADs engaging distinct interfaces of the same cofactor or cofactor complex can cooperate to achieve efficient recruitment, even when individual interactions are weak.

To test this experimentally, we designed p300 KIX binders with affinities ranging from nano- to micromolar and measured their transcriptional activity. We found a switch-like response around 500 nM! Stronger binding beyond this threshold provided little additional activation.

We first used AF3 to systematically map interactions between TADs and transcriptional cofactors. Interestingly, the predictions revealed distinct cofactor-binding preferences. Some cofactors were highly selective, whereas others showed broader interaction profiles.

Guided by these predicted interfaces, we used RFdiffusion to design proteins that specifically bind cofactors. Using a functional screen in cells, we identified more than 300 binders across 10 cofactors! These binders allow us to recruit cofactors individually or in combination.

TFs recruit cofactors through transcriptional activation domains (TADs). These domains are often intrinsically disordered and engage cofactors through weak, promiscuous interactions. This makes it difficult to dissect and precisely control gene activation.

Will Chen reposted

Jay Shendure

@jshendure.bsky.social

30 July

New preprint from Shendure Lab on Locus-Scale aka Long-@$$ MPRAs led by the amazing Abby McGee & @carinabiar.bsky.social Most MPRAs test ~300 bp fragments next to a promoter. But real enhancers are bigger, act combinatorially and from a distance. 1/n www.biorxiv.org/content/10.6...

@troymcdiarmid.bsky.social

13 Feb

We have significantly improved the protocol for recording CRE activities and orders with ENGRAM. We also designed new plasmids for easier cloning. Great work with @jennynathans.bsky.social, @troymcdiarmid.bsky.social and @jshendure.bsky.social . Happy recording!!

Jenny Nathans@jennynathans.bsky.social

Super happy to share our protocol for ENGRAM is out in Nature Protocols! This was fun to write with @chenomics.bsky.social @troymcdiarmid.bsky.social @jshendure.bsky.social. In it we describe how to record CRE identity, activity, and order in mammalian cells.

Will Chen reposted

Troy McDiarmid

12 Nov 2025

Our work developing a parts list of promoters and gRNA scaffolds for mammalian genome engineering and molecular recording is now out @natbiotech.nature.com

Nature Biotechnology@natbiotech.nature.com

A parts list of promoters and gRNA scaffolds for mammalian genome engineering and molecular recording - @jshendure.bsky.social @troymcdiarmid.bsky.social @uwgenome.bsky.social go.nature.com/49eTPCu

go.nature.comA parts list of promoters and gRNA scaffolds for mammalian genome engineering and molecular recording - Nature BiotechnologyPrime editing in mammalian cells benefits from a comprehensive list of genetic parts.

6 May 2025

Molecular recording is a exciting and rapidly evolving field. In this perspective, @choijunhong.bsky.social and I delve into the key challenges in the field and highlight a few exciting frontiers that worth more attention.

Trends in Genetics@cp-trendsgenetics.bsky.social

Online now -- a new Review: "Molecular circuits for genomic recording of cellular events" by Wei Chen & Junhong Choi (@choijunhong.bsky.social) FREE to read till June 25th using this link: authors.elsevier.com/a/1l2gMcQbJF...

taming-the-beast.orgApplication deadline extended for Taming the BEAST in Beijing!

6 May 2025

We are thankful to Jay @jshendure.bsky.social for his constructive feedback, and to the funding agency @damonrunyon.org for the support. It's always fun to work with Choi, looking forward to more collaborations in the future.

Will Chen reposted

Sophie Seidel

@seidels.bsky.social

17 Apr 2025

Interested in #Bayesian #phylogenetics? 🧬 Join the Taming the BEAST workshop — theory + hands-on tutorials incl. #singleCell, #devBio & #lineageTracing! 📍Beijing, July 14–18, 2025 📅 Apply by April 25 I'll teach on TiDeTree & cell trees 🔗 taming-the-beast.org/news/Deadlin...

Will Chen reposted

Vijay Ramani

@vram142.bsky.social

15 Nov 2024

The latest from our group, led by Megan Ostrowski and @martyyang.bsky.social, is now published in final form (www.cell.com/cell/fulltex...! Many thanks to our excellent peer reviewers for suggesting several experiments (including CAF-1 perturbation) to really improve the study =) #epigenetics

cell.comThe single-molecule accessibility landscape of newly replicated mammalian chromatinBy developing a long-read sequencing method to simultaneously map replication status and protein-DNA contacts in cells, Ostrowski, Yang, et al. show that newly replicated chromatin is enriched for unw...