Jay Shendure

Two new preprints from the @arjunraj.bsky.social‬ on #gastruloids. Both excellent. Exploring the relationship between macroscopic reproducibility v microscopic heterogeneity. Stunning experiments and much to think about
biorxiv.org/content/earl...
biorxiv.org/content/earl...

🚨 Most variant screens measure growth or abundance. What do they miss? That variants impact a spectrum of protein and cellular phenotypes. Variant in situ sequencing (VIS-seq) finds what’s missing: image cells 🔬 first, decode later, revealing multi-scale phenotypes for thousands of variants.👇

1/9

One thing that really bothers me with the new "virtual cell" terminology is that it is currently largely focused on a very narrow definition of models that can predict effects of trans perturbations (gene dosage, drugs etc) on gene expression. 1/

Lineage-resolved analysis of embryonic gene expression evolution in C. elegans and C. briggsae The constraints that govern the evolution of gene expression patterns across development remain unclear. Single-cell RNA sequencing can detail these constraints by systematically profiling homologous ...

Lineage-resolved analysis of embryonic gene expression evolution in C. elegans and C. briggsae | Science www.science.org/doi/10.1126/... 😍

EPIGENETIC HULK READY TO SMASH AGAIN! GET IN LOSERS!

Barcoded monoclonal embryoids are a potential solution to confounding bottlenecks in mosaic organoid screens Genetic screens in organoids hold tremendous promise for accelerating discoveries at the intersection of genomics and developmental biology. Embryoid bodies (EBs) are self-organizing multicellular str...

Expanding Perturb-seq-like screens to multicellular systems also increases the complexity of confounding effects. We encountered this when we perturbed all TFs in mosaic embryoid bodies (EBs) and develop a scalable solution by barcoding monoclonal individuals. 🧵 www.biorxiv.org/content/10.1...

Lineage recording in monoclonal gastruloids reveals heritable modes of early development Mammalian stem cells possess a remarkable capacity for self-organization, a property that underlies increasingly sophisticated in vitro models of early development. However, even under carefully contr...

New preprint with the Shendure lab @jshendure.bsky.social ! We apply the DNA Typewriter lineage recorder to mouse 3D gastruloids, a powerful model of early mammalian development. Led by Sam Regalado and CX Qiu @cxqiu.bsky.social : www.biorxiv.org/content/10.1... (1/13)

A multi-kingdom genetic barcoding system for precise clone isolation - Nature Biotechnology A barcoded CRISPR base editing system isolates target clones from complex mammalian, yeast and bacterial populations.

CloneSelect published in Nature Biotechnology
@natbiotech.nature.com. This retrospective clone isolation method using CRISPR base editors is a powerful tool in broad biology. A history of Soh in the Yachie lab. www.nature.com/articles/s41...

Massively parallel jumping assay decodes Alu retrotransposition activity - Nature Communications Here, the authors develop a high-throughput assay to measure the jumping potential of thousands of transposons in parallel.

Massively parallel jumping assay (MPJA) enables to test the jumping potential of thousands of transposons. Analysis of >160,000 Alu haplotypes identified transposition-asssociated domains. Amazing work by Navneet Matharu, Jingjing Zhao, Martin Kircher and many others.
www.nature.com/articles/s41...

SEARLE SCHOLARS PROGRAM NAMES 15 SCIENTISTS AS SEARLE SCHOLARS FOR 2025 Members of the new class of Searle Scholars pursue ground-breaking research in chemistry and the biomedical sciences. Each receives an award of $300,000 in flexible funding to support his, her, or …

Very grateful to receive the Searle Scholars Award, especially during this challenging time! This support will help our lab realize our vision of genomic recording for reconstructing the mammalian cell fate decision. searlescholars.org/2025/04/14/s...

Happy to share our new review on molecular circuits for genomic recording with @chenomics.bsky.social! Here, we present our views on the remaining challenges in the field of genomic recording for reconstructing cell-fate decisions. (1/2)

Junior / Assistant Specialist: Kim Lab, Developmental & Cell Biology University of California, Irvine is hiring. Apply now!

I am hiring for a research technician role in my new lab at UC Irvine studying how transcription factors control cell identity. If you know any graduating undergrads or postbacs looking for a position, please spread the word! Apply by May 9 for full consideration. recruit.ap.uci.edu/JPF09594

CREsted: modeling genomic and synthetic cell type-specific enhancers across tissues and species Sequence-based deep learning models have become the state of the art for the analysis of the genomic regulatory code. Particularly for transcriptional enhancers, deep learning models excel at decipher...

Very proud of two new preprints from the lab:
1) CREsted: to train sequence-to-function deep learning models on scATAC-seq atlases, and use them to decipher enhancer logic and design synthetic enhancers. This has been a wonderful lab-wide collaborative effort. www.biorxiv.org/content/10.1...

Bioscience Funding Confusion Threatens U.S. Innovation ‘With the current turmoil, China could surpass the U.S. in the near future,’ Nobel Prize winner David Baker warns.

‘With the current turmoil, China could surpass the U.S. in the near future,’ Nobel Prize winner David Baker warns
www.wsj.com/articles/bio...

Big news: we are setting up a new non-profit organization to run bioRxiv and medRxiv. It's called openRxiv [no it's not a new preprint server; it's dedicated organization to oversee the servers] openrxiv.org 1/n

We're expediting sex designation change requests on birth certificates. People born in WA who want to change the sex designation on their birth certificate can do so by filing a request with us. . doh.wa.gov/DesignationC...

It’s been a tough few weeks. My 10yo daughter was diagnosed with a very rare, aggressive cancer called interdigitating dendritic cell sarcoma (IDCS). I’m reaching out to identify clinicians/patients who have encountered pediatric IDCS or other (non-LCH) dendritic or histiocytic sarcomas cases.

Section 224 of Public Law (PL) 118–47 as carried forward by PL 118-158: SEC. 224. In making Federal financial assistance, the provisions relating to indirect costs in part 75 of title 45, Code of Federal Regulations, including with respect to the approval of deviations from negotiated rates, shall continue to apply to the National Institutes of Health to the same extent and in the same manner as such provisions were applied in the third quarter of fiscal year 2017. None of the funds appropriated in this or prior Acts or otherwise made available to the Department of Health and Human Services or to any department or agency may be used to develop or implement a modified approach to such provisions, or to intentionally or substantially expand the fiscal effect of the approval of such deviations from negotiated rates beyond the proportional effect of such approvals in such quarter.

Here's a very important update from the AAMC (Association of American Medical Colleges) on the proposed cuts to NIH Indirect costs: "Every year since 2017, the annual spending bill that funds NIH has included language prohibiting the Administration from making changes to F&A cost rates" 1/2 🧪

🧬@science.org Multiplex generation and single-cell analysis of structural variants in mammalian genomes bit.ly/4hzFRMg @sudpinglay.bsky.social www.pinglay-lab.com @jshendure.bsky.social et al. @brotmanbaty.bsky.social @hhmi.bsky.social #synbio #genome

Multiplex generation and single-cell analysis of structural variants in mammalian genomes Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) ...

Now out in @science.org w/ @jshendure.bsky.social we present 'Genome-shuffle-seq': a method to shuffle mammalian genomes and characterize the impact of structural variants (SVs) with single-cell resolution in one experiment.

www.science.org/doi/10.1126/...

Multiplex generation and single-cell analysis of structural variants in mammalian genomes Studying the functional consequences of structural variants (SVs) in mammalian genomes is challenging because (i) SVs arise much less commonly than single-nucleotide variants or small indels and (ii) ...

This project stands together with work from @sudpinglay.bsky.social and @jshendure.bsky.social , who came up with an alternative method that includes a clever, single-cell sequencing strategy to read out the variants generated by scrambling.
www.science.org/doi/10.1126/...

Genome recombination on demand Large genome rearrangements in mammalian cells can be generated at scale

Lars Steinmetz and @seczmarta.bsky.social put together a wonderful perspective on these two studies. www.science.org/doi/10.1126/...

Randomizing the human genome by engineering recombination between repeat elements We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into re...

We're delighted to share our work on scrambling the human genome using prime editing, repetitive elements, and recombinases in @science.org , led by @jonaskoeppel.bsky.social , @f-raphael.bsky.social , with @proftomellis.bsky.social and George Church.
www.science.org/doi/10.1126/...

Beware! AAV libraries prone to length & homology dependent chimerism! Our latest preprint, from the brilliant @jblalanne.bsky.social‬, was a true surprise as related phenomena are textbook for lentivirus (highly relevant to HIV & Perturb-seq) yet to our reading not known for AAV tinyurl.com/5amc562a

Brief PSA for the functional genomics community: if you are profiling complex libraries with >1 internal components (e.g., enhancer+barcodes in MPRAs) delivered via AAVs, be aware that there might be substantial unlinking within your libraries if you packaged as a pool! doi.org/10.1101/2025...

Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease Single-cell measurement of the Huntington’s disease-causing CAG repeat reveals that somatic expansion of this repeat drives pathological changes in neurons, providing insights into disease progression...

I started working on genetic therapies for Mendelian disease in 2000 - and in the subsequent 25 years have never seen a disease where the molecular aetiology has undergone as giant an "OH WOW" moment as this.
www.cell.com/cell/fulltex...

Enhancer scrambling strategy

We are happy to share our enhancer scramble story, a strategy to create hundreds of stochastic deletions, inversions, and duplications within mammalian gene regulatory regions and associate these new architectures with gene expression levels 🧵
www.biorxiv.org/content/10.1...

Massively parallel characterization of transcriptional regulatory elements - Nature Lentivirus-based reporter assays for 680,000 regulatory sequences from three cell lines coupled to machine-learning models lead to insights into the grammar of cis-regulatory elements.

Massively parallel reporter assays (MPRAs) testing >680,000 sequences combined with machine learning to improve regulatory element & variant effect prediction. Amazing work by @vagar.bsky.social, Fumitaka Inoue, @jshendure.bsky.social and many others as part of ENCODE.
www.nature.com/articles/s41...

The regulatory grammar of human promoters uncovered by MPRA-trained deep learning One of the major challenges in genomics is to build computational models that accurately predict genome-wide gene expression from the sequences of regulatory elements. At the heart of gene regulation ...

Haven't tried it but this one from Bas van Steensel's group is trained based on MPRA data (I can buy the arguments for why that would be helpful) and at least appears to at least be lightweight - www.biorxiv.org/content/10.1...