Early Career Faculty Program | Freeman Hrabowski Scholars | HHMI The Freeman Hrabowski Scholars Program offers comprehensive support to outstanding early career faculty committed to scientific excellence in their own research, and to fostering labs that expand the ...

@hhmi-science.bsky.social's
#FreemanHrabowski Scholars Program offers early career faculty up to $10M over 10 yrs, plus salary & benefits

Stable, sustained support can transform your career:

Senior Postdoc? This year's competition has a program for you too. Applications open 11/3! bit.ly/4vhC0LA

HHMI CEO: "diamond funding should be deployed to sustain repositories [i.e. preprint servers] and connective infrastructure that focus on researcher-shared outputs" zenodo.org/records/1960...

Excited to share our new paper @nature.com! We developed PerturbFate, a scalable single-cell platform to discover how diverse genetic perturbations converge on a shared drug-resistant cell state, and key programs driving it, led by our incredible Zihan Xu from @rockefeller.edu
rdcu.be/fdC14

CREsted is finally out! You can find the article, together with a summarizing Research Briefing, in thread. 🦎

Evolutionary transfer learning enables organism-wide inference of mammalian enhancer landscapes Understanding and modeling how the human genome encodes gene regulatory programs for thousands of cell types remains a central challenge in genomics and machine learning. However, most human cell types emerge during embryonic, fetal, and pediatric development which are inaccessible to comprehensive molecular profiling. To overcome this, we hypothesized that the mismatch in evolutionary rates between cis-acting enhancers (fast) and the trans-acting regulatory programs that interpret them (slow) creates an opportunity for ‘evolutionary transfer learning’. Specifically, models trained to predict cell type-specific enhancers in one species should generalize to the orthologous cell types and enhancers of related species. To test this, we generated a single-cell atlas of chromatin accessibility spanning mouse embryonic day 10 (E10) to birth (P0). Using combinatorial indexing1, we profiled 3.9 million nuclei from 36 staged embryos, resolving genome-wide accessibility in 36 cell classes and 140 cell types. With the goal of identifying distal enhancers for all cell classes, we trained a series of multi-output deep learning models (CREsted2), each addressing limitations of the preceding approach. An ‘evolution-naive’ model achieves strong performance on heldout peaks, but exhibited two failure modes during genome-wide inference: overprediction at tandem repeats and conflation of promoter and distal enhancer grammars. An ‘evolution-aware’ model resolves these by regrouping accessible regions based on functional coherence across syntenic orthologs, but fails to generalize across species — suggesting insufficient sequence diversity during training. Finally, STEAM (Synteny-aware Transfer learning for Enhancer Activity Modeling), our ‘evolution-augmented’ model, expands the training corpus to include enhancer orthologs from up to 241 mammalian genomes (Zoonomia3) in a synteny-supervised manner. This increases the effective data scale by up to 195-fold, markedly improving generalization across mammals despite greater label noise. We apply STEAM predict enhancers for all major developmental lineages throughout the human, mouse (HumMus) and 239 additional mammalian genomes3 (BabaGanoush), i.e. 32 × 241 = 7,712 genome-wide enhancer tracks. Together, our results unify advances in single-cell profiling, deep learning, and comparative genomics into a framework for the evolutionary transfer learning of noncoding regulatory grammars. More broadly, our work supports the view that model organisms and evolutionarily diverse genomes are indispensable resources for accelerating the AI-enabled exploration of human biology.

In addition to the bioRxiv this is also pilot for a new interactive preprint developed by @curvenote.com w/ support from @hhmi-science.bsky.social including directly embedded Jupyter notebooks for fig reproduction, data, models, prediction tracks, code, etc
shendure.curve.space/articles/evo...

A more detailed thread on the paper below from @cxqiu.bsky.social.

bsky.app/profile/cxqi...

It took some doing, but the resulting STEAM model predicts genome-wide distal enhancer landscapes for hard-to-obtain cell types throughout the human genome, despite not being trained on any human molecular data, as well as 240 other mammalian genomes. Here shown for alpha-fetoprotein/albumin locus.

Latest from Shendure & Qiu labs (@cxqiu.bsky.social)
)! We combined a new 4M cell mouse whole embryo scATAC-seq atlas (E10-P0), millions of 'evolutionarily coherent' orthologs from 241 mammalian genomes (Zoonomia), and the CREsted CNN framework (@steinaerts.bsky.social).

New preprint @cxqiu.bsky.social @jshendure.bsky.social ! Can we learn regulatory grammars of human cell types — by training on mouse development and transferring across 241 mammalian genomes? Introducing STEAM & a whole-organism scATAC-seq atlas from E10 to birth.
www.biorxiv.org/content/10.6...

Stoked to announce that I’m starting a lab as an Assistant Professor in the School of Biomedical Engineering and Centre for Brain Health at UBC!

mcdiarmid-lab.sbme.ubc.ca

Recruiting at all levels - please share the word!

Cheers and happy long weekend all!

1/ 🚀 Excited to release: napari-mcp - agentic control of napari from any MCP-capable AI assistant!
Use it for interactive image processing, analysis, and visualisation! Really cool project from @ilan-theodoro.bsky.social from my team!
#napari #bioimageanalysis #MCP @biohub

AP-1 mediates cellular adaptation and memory formation @natcomms.nature.com @pennmedicine.bsky.social
@arjunraj.bsky.social @penngenetics.bsky.social
www.nature.com/articles/s41...

Nitrogen, Ammonia, and the Strait of Hormuz

I mean, these are always good. But this is So Good.

Nitrogen, Ammonia, and the Strait of Hormuz | Science | AAAS www.science.org/content/blog...

Whole-embryo spatial transcriptomics at subcellular resolution from gastrulation to organogenesis Gene expression patterns underlie development, but their systematic detection in whole embryos has remained elusive. We introduce a whole-embryo imaging platform using multiplexed error-robust fluores...

Very happy to see this out. 👏 @yinanwan.bsky.social
Bogdan Bintu and team.
Whole-embryo spatial transcriptomics at subcellular resolution from gastrulation to organogenesis | free link Science www.science.org/eprint/5MHTM...

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!!

Mammalian genome writing: Unlocking new length scales for genome engineering The ability to design and engineer mammalian genomes across arbitrary length scales would transform biology and medicine. Such capabilities would enab…

Happy to share that our review on mammalian genome writing with Jack Atwater, Ran Brosh, Jef Boeke, @jshendure.bsky.social and Matt Maurano is now out in @cellpress.bsky.social!

www.sciencedirect.com/science/arti...

Summer Undergraduate Research Experience | HHMI The Cech Fellows Program is a paid, nine-week summer research experience empowering the next generation of scientific leaders.

Calling all rising juniors & seniors: Interested in biological or biomedical research? Applications for our ’26 Summer Undergraduate Research Experience Program are now open! Nine weeks, hands-on research, & mentorship from some of the nation’s top scientists — learn more: bit.ly/CechFellows

Happy Birthday to the Seattle Hub for Synthetic Biology! 🎂🎉

OTD with @chanzuckerberg.bsky.social and @uwmedicine.bsky.social, we launched #SeaSynBio with the goal to build tech that allows cells to record their own histories.

🔗 alleninstitute.org/division/seattle-hub-for...

Widespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCs Low-affinity transcription factor (TF) motifs are an important element of the cis-regulatory code, yet they are notoriously difficult to map and mechanistically incompletely understood, limiting our a...

We are pleased to announce a new preprint by @mlweilert.bsky.social: “Widespread low-affinity motifs enhance chromatin accessibility and regulatory potential in mESCs” (www.biorxiv.org/content/10.1...). See summary and longer recap below:

(TLDR; low-affinity motifs matter as pioneers!)

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

A parts list of promoters and gRNA scaffolds for mammalian genome engineering and molecular recording - Nature Biotechnology Prime editing in mammalian cells benefits from a comprehensive list of genetic parts.

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

🚀 Very excited to share the first major work from my PhD!!

We combined MPRA and CRISPRa in excitatory neurons to test and validate cis-regulation therapies for hundreds of haploinsufficient neurodevelopmental disorder genes. 🧬🔬

www.biorxiv.org/content/10.1...

Stoked to share our latest work entitled: “Large-scale discovery of neural enhancers for cis-regulation therapies”

shorturl.at/H3Qww

This is an enormous team effort that I had the honour of spearheading with Nick Page and Florence Chardon.

Bluetorial below.

Thrilled to share I’ve started my lab at Dartmouth’s Geisel School of Medicine! We focus on mapping cellular trajectories & TF networks in development and Mendelian disorders, exploring new therapies. Join us—postdocs, grads, and scientists welcome! sites.dartmouth.edu/qiulab/

Hierarchical lineage architecture of human and avian spinal cord revealed by single-cell genomic barcoding The formation of neural circuits depends on the precise spatial and temporal organisation of neuronal populations during development. In the vertebrate spinal cord, progenitors are patterned into mole...

Thrilled to share my main postdoc work with @jamesbriscoe.bsky.social

We used genomic barcoding + scRNAseq in chick & human embryos to reveal a lineage architecture that reshapes how we understand neural tube development & cell fate decisions
🧵👇

www.biorxiv.org/content/10.1...

This is one of the coolest figures I've seen in a while

Super excited about first Shendure/Baker Lab collaboration & preprint on a multiplex sequencing-based strategy for screening de novo proteome editors in mammalian cells. Kudos to the brilliant Chase Suiter (not here) & @greenahn.bsky.social on the work! Preprint here:
www.biorxiv.org/content/10.1...

There is also no space bar 😢

Developmental Biology and Disability.

“Developmental biology is fundamentally beautiful. We are no less beautiful for our variation. Instead, perhaps we are more so. Perhaps we are remarkable. Perhaps we are full of wonder.”

Insightful post by Bethan ⬇️👀
thenode.biologists.com/developmenta...

ATP-dependent remodeling of chromatin condensates reveals distinct mesoscale outcomes Adenosine triphosphate (ATP)–dependent chromatin remodeling enzymes mobilize nucleosomes, but how such mobilization affects chromatin condensation is unclear. We investigate effects of two major remod...

awesome new work by my @gladstoneinst.bsky.social and @ucsanfrancisco.bsky.social colleagues incl @vram142.bsky.social on how chromatin remodelers affect mesoscale chromatin organization www.science.org/doi/10.1126/...