Beautiful work @cxqiu.bsky.social @jshendure.bsky.social and co.!

Thank you!

@sbmeubc.bsky.social @dmcbrainhealth.bsky.social

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!

New preprint from our lab where we learn some interesting things about the context specificity of TFs in their regulation of gene expression by dissecting MPRA-trained sequence-expression models. Surprising guest appearance from RNA Pol III(!) Thread from 1st author @sambean12.bsky.social 👇

Harnessing heterogeneity for the rational design of cell manufacturing Dorri Nokoorani et al. argue that heterogeneity can be harnessed as a design feature in the quality-by-design toolkit to optimize the yield, quality, and robustness of bioprocesses for manufacturing s...

[Plz 📢] A little late to the party, but check out our perspective on how cellular heterogeneity can be your friend😊 or foe😠 in cell therapy manufacturing🧫. Shout out to Yeganeh, Hourieh, Enzo, Ali, Yonatan: www.cell.com/cell-systems... @sbmeubc.bsky.social

We wrote a perspective "How to build the regulatory genome: a constructionist guide to the cis-regulatory code", out in Development yesterday. Title says it all. Find it here:

journals.biologists.com/dev/article/...

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!!

Check out our new protocol paper on molecular recording of transcriptional events in genomic DNA!

Super fun pulling this together with @jennynathans.bsky.social @chenomics.bsky.social and @jshendure.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.

Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, ...

Together with @ronghuizhu.bsky.social, we are thrilled to present our new perturb-seq study of 22M primary CD4+ T cells, across donors and timepoints – the result of a decade-long collaboration between the Marson @marsonlab.bsky.social and Pritchard @jkpritch.bsky.social labs 🧵 tinyurl.com/gwt2025

We added several additional experiments using the parts to target alternate loci, measure both transcription and editing, and more.

Great experience working on this with Megan Taylor , @jshendure.bsky.social and co. and very rewarding to see the rapid uptake by the community. Cheers!

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

🚀 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...

Thanks Sreeparna!

Thanks to all co-authors on and off bluesky, especially @nadavahituv.bsky.social and @jshendure.bsky.social, as well as the funders and families. Cheers!

Our results provide a comprehensive resource of active, target-linked human neural enhancers for NDD genes and gRNA reagents for CRT development. More broadly, this work establishes a generalizable strategy for discovering CRT gRNA candidates across cell types and haploinsufficient disorders.

Finally, we confirmed that several of the CRISPRa gRNAs identified here demonstrated selective and therapeutically relevant upregulation of SCN2A, CHD8, CTNND2 and TCF4 when delivered virally to patient cell lines, human cerebral organoids, and a humanized mouse model of hTcf4.

We identified hundreds of promoter- and enhancer-targeting CRISPRa gRNAs that upregulated 200 of the 337 NDD genes in human neurons, including 91 novel enhancer-gene pairs.

Next, we applied multiplex single-cell CRISPRa screening with 15,643 gRNAs to test all MPRA-prioritized cCREs and 761 promoters of NDD genes in their endogenous genomic contexts.

We then tested all 5,425 candidate neuronal enhancers with MPRA, identifying 2,422 that are active in human neurons.

We first prioritized 337 haploinsufficient NDD risk genes from 42,320 cases. We then nominated 5,425 candidate enhancers for these 337 genes leveraging multiple datasets characterizing the regulatory landscape of the developing human brain, together with various enhancer-gene mapping strategies.

Here, we combined Massively Parallel Reporter Assays (MPRAs) and a multiplex single cell CRISPRa screen to discover functional human neural enhancers whose CRISPRa targeting yields specific upregulation of NDD risk genes.

However, scaling this cis-regulatory therapy (CRT) paradigm requires pinpointing which candidate cis-regulatory elements (i.e. promoters and enhancers) are active in human neurons, and which can be targeted with CRISPRa to yield specific and therapeutic levels of target gene upregulation.

Many neurodevelopmental disorders are caused by haploinsufficiency - where functional loss of one gene copy leaves insufficient expression from the other.

CRISPR-based gene activation (CRISPRa) has emerged as a promising therapeutic approach for NDD caused by haploinsufficiency.

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/

Sometimes I think about how from 1935-1975ish, Bell Labs produced an insane amount of revolutionary science and technology, including 11 Nobel Prizes, the transistor, UNIX, C, the laser, the solar cell, information theory, etc. The secret? Provide scientists with ample, steady, no-strings funding.

Check out MitoScribe in our new preprint led by Linhan Wang: www.biorxiv.org/content/10.1...

It's an analog molecular recorder that uses neutral base edits to the mitochondrial genome to store information about historical signaling in a cell. Single cell resolution at scale (see next post)!

E11 Bio is excited to unveil PRISM technology for mapping brain wiring with simple light microscopes. Today, brain mapping in humans and other mammals is bottlenecked by accurate neuron tracing. PRISM uses molecular ID codes and AI to help neurons trace themselves.

Read more: e11.bio/blog/prism