Troy McDiarmid

🚀 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

After 10 years of work, a complete telomere-to-telomere gap-free genome for C. elegans finally exists: it has 106 Mb rather than the textbook 100.3 Mb, and up to 366 additional genes.
genome.cshlp.org/content/35/8...

I'll never get tired of these.

(courtesy of Sebasitan Wittekindt doi.org/10.1101/2025...)

Beautiful!

Well don't I feel stupid

New paper from my lab and @jshendure.bsky.social lab! Led by the brilliant @zukailiu.bsky.social and @cxqiu.bsky.social. We tackled how anterior and posterior progenitor cells cooperate to self-organize into an embryonic structure (termed AP-gastruloid). (1/n) www.biorxiv.org/content/10.1...

Functional maps of a genomic locus reveal confinement of an enhancer by its target gene Genes are often activated by enhancers located at large genomic distances, and the importance of this positioning is poorly understood. By relocating promoter-reporter constructs into thousands of alt...

✨Exciting news: the main story of my PhD is out in Science!

Together with Christine Moene @cmoene.bsky.social, we explored what happens when you scramble the genome—revealing how Sox2’s position shapes enhancer activation.

📖 Read the full story here: www.science.org/doi/10.1126/...

bioRxiv - An unbiased survey of distal element-gene regulatory interactions with direct-capture targeted Perturb-seq

New preprint from our lab!

What can we learn about the properties of gene regulatory elements by CRISPR’ing a random set of accessible sites in human cells?

Find out here: www.biorxiv.org/content/10.1...

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Genetic and epigenetic screens in primary human T cells link candidate causal autoimmune variants to T cell networks - Nature Genetics Massively parallel reporter assay in primary human CD4+ T cells and bulk and single-cell CRISPR-interference screens identify candidate causal variants linked to autoimmune disease risk that modulate ...

Excited to finally present the lab's latest work in defining candidate causal genetic variants that drive autoimmune diseases and their effects on primary human T cell expression and function! www.nature.com/articles/s41...

CRISPR activation for SCN2A-related neurodevelopmental disorders Nature - Using SCN2A haploinsufficiency as a proof-of-concept, upregulation of the existing functional gene copy through CRISPR activation was able to rescue neurological-associated phenotypes in...

SCN2A loss is strongly linked to neurodevelopmental delays and, at times, seizure. In an amazing collaboration with @nadavahituv.bsky.social, led by Serena Tamura, Andrew Nelson, and Perry Spratt, we leveraged CRISPR activator approaches to rescue this loss.

rdcu.be/eGU0W

Google and Meta search both report that Cape Breton Island has its own time zone 12 minutes ahead of mainland Nova Scotia time because they are both drawing that information from a Beaverton article I wrote in 2024

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...

Congrats @nzmyachie.bsky.social and co.! Beautiful work.

CAGT Poster featuring Keynote, Dr. Calin Plesa, of DropSynth fame!

⏰Abstract deadline for the Cascadia Advanced Genomic Technologies Meeting is April 30!⚠️ We're hoping this will be the first of many, catalyzing collaboration and leveraging our regional strength in advanced genomics technologies! See you there!
de-boer-lab.github.io/CAGT_meeting/