@wchenomics

@DamonRunyon Fellow at Baker lab @UWproteindesign. PhD with @JShendure. mainly at https://xitter.cf/t.co/WpSk6RTizP

 Seattle, WA
chenomics.com
Joined October 2013
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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!
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Numerous biotech innovations started with adapting a protein to its non-native context, which often requires substantial experimental optimizations. Here’s a breakdown by our lead, @Xiaowei0402, on a versatile, efficient computational framework to facilitate such adaptations.
Xiaowei Zhang
@Xiaowei0402Oct 20
We deimmunized a clinical CD19 CAR binder with experimentally detected HLA-I epitope depletion while retaining tumor killing, and rescued a secreted protease to function in the cytosol. Both done with one unified design framework: ProVADA. How it works and what we tested 🧵 (1/11)
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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.
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I would like to thank David @uwproteindesign for his support and guidance. and @ruopu22 @kinasekid @isaacbhilton and other x-free authors for their help and discussions.
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And most importantly, I need to thank @DamonRunyon for their support on this risky project!
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RFD4 is amazing!
Kieran Didi
@DidiKieranOct 21
Avengers assemble: 1 year BakerLab + NVIDIA GenAIR = 🔥 rfd4-proteina.org Presenting RFD4-Proteina, our latest protein design model, significantly better and faster than everything we compared against, both in silico and in the lab! 1/30
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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.
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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.
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biorxiv.org/content/10.64898…

Design of synthetic activators for programmable gene expression

Transcription factors control gene expression by recruiting transcriptional coactivators through intrinsically disordered transcriptional activation domains (TADs), whose weak and promiscuous...

biorxiv.org
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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.
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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.
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Will Chen retweeted
HHMI
@hhmi_scienceOct 8
Every cell in our body comes from 1 fertilized egg — & now we can trace that dev. #HHMIInvestigators Jonathan Weissman & Jay Shendure & teams have created new tools that generate maps of the origin & outcome of vast numbers of cells in a developing mouse: bit.ly/4dVhnhe
Two stacked portraits. Top: HHMI Investigator Jonathan S. Weissman of the Whitehead Institute for Biomedical Research smiles in a research lab, wearing glasses and a white lab coat with “Weissman” stitched on the chest. Pipettes and lab equipment fill the bench beside him. Bottom: HHMI Investigator Jay Shendure of the University of Washington smiles at his desk, wearing glasses and a gray collared shirt with a small clip-on microphone. Behind him are framed photos, a child’s drawing pinned to the wall, and a computer monitor displaying lines of green text on a dark terminal window.

ALT Two stacked portraits. Top: HHMI Investigator Jonathan S. Weissman of the Whitehead Institute for Biomedical Research smiles in a research lab, wearing glasses and a white lab coat with “Weissman” stitched on the chest. Pipettes and lab equipment fill the bench beside him. Bottom: HHMI Investigator Jay Shendure of the University of Washington smiles at his desk, wearing glasses and a gray collared shirt with a small clip-on microphone. Behind him are framed photos, a child’s drawing pinned to the wall, and a computer monitor displaying lines of green text on a dark terminal window.

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What a wonderful day for recording community! Such beautiful paired work mapping the lineage from embryo to mouse! Let's decorate some "trees"
Jay Shendure@JShendureOct 8
Exciting day for DNA Typewriter w/ 2 papers from the lab & SeaHub out today :) 1. Mouse lineage from E0 to E13.5 science.org/doi/10.1126/scie… 2. A fluctuation test for gastruloid heterogeneity cell.com/cell/fulltext/S0092… Paper #1 covered in quoted thread. More on paper #2 here. 1/n

A DNA Typewriter records the cell lineage history of a mouse, from zygote to late organogenesis

Mammalian biology unfolds over time, within tissues and organs opaque to our eyes and instruments. We applied DNA Typewriter, a sequential molecular recorder, to record the cell lineage of a mouse...

science.org
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Excited to share Shotgun Genetic Engineering, developed by @julie_trolle, out in @NatureBiotech! Read on to learn how Julie enabled mammalian cells to grow without 2 essential amino acids for the first time in >500 million years using highly multiplexed metabolic engineering!
Nature Biotechnology
@NatureBiotechOct 6
Highly multiplexed mammalian metabolic engineering with a shotgun approach - @sudpinglay @JefBoeke nature.com/articles/s41587-0…
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Will Chen retweeted
Jay Shendure@JShendureJul 31
Thrilled to post thread re: new single-cell lineage of mouse embryo reconstructed w/ DNA Typewriter. One animal, zygote to late organogenesis (E13.5). Tree has 1,340,794 transcriptionally profiled, annotated tips (cells), 1,142,588 dated internal nodes, rooted at zygote 1/n
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Could the folding of synthetic gene circuits in 3D shape how genes are expressed? Today @ScienceMagazine we report on the role of gene syntax in shaping feedback between transcriptional activity and genome folding for advanced circuit design🧵 (1/n)
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New preprint! @JShendure @CXchengxiangQIU Can we learn regulatory grammars of human cell types we'll never be able to profile - by training on mouse development and transferring across 241 mammalian genomes?biorxiv.org/content/10.64898…
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Our Human Multiomic Development Atlas paper is out in Nature today! A heart-felt "thank you" to all co-authors for their tireless work on this complex yet exciting project! Congrats all! nature.com/articles/s41586-0…

Multiomics and deep learning dissect regulatory syntax in human development

Nature - The Human Development Multiomic Atlas catalogues single-cell accessibility and gene expression data from human fetal cells across 12 organs, enabling the inference of syntactic rules for...

nature.com
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