Thread by @gokcen

We are very excited to share our single-nucleus cross-tissue atlas w/ Eugene Drokhlyansky, @francoisaguet, @ShankaraKAnand, @ayshwaryas, @EvgenijFiskin, @asegre, Orit Rozenblatt-Rosen, @KArdlie, Aviv Regev and many others 1/n

We applied four snRNA-seq methods to each of 25 samples from 8 banked GTEx tissues, 16 donors, generating a cross-tissue atlas of 209,126 nuclei profiles
2/n

We integrated across individuals and protocols using a conditional β-TCVAE. We captured difficult-to-profile and rare cell types e.g. adipocytes, skeletal muscle myocytes, including an NMJ-rich state, cardiomyocytes, ICCs, enteric neurons and neuroendocrine cells 3/n

We benchmarked nuclei profiles from four protocols vs. scRNA-seq of comparable fresh tissues and other snRNA-seq datasets which showed high concordance, with some benefits for snRNA-seq such as the lack of dissociation signatures 4/n

We compared myeloids across 8 tissues and highlighted tissue-restricted and non-restricted resident macrophage populations including a cross-tissue conserved dichotomy between LYVE1- and HLA class II-expressing macrophages. 5/n

We also highlighted the broad presence of LAM-like macrophages across healthy tissues that is also observed in diseases such as leprosy, acne, atherosclerosis and Crohn's disease. We further infer the TFs involved in lipid metabolism-related pathways activated in LAMs 6/n

For rare, monogenic muscle diseases, we identified cell types that likely underlie the neuromuscular, metabolic, and immune components of these diseases, and biological processes involved in their pathology, including Schwann cells, neurons, and adipocytes 7/n

For common complex diseases and traits analyzed by GWAS, we identified the cell types that potentially underlie disease mechanisms w/ 2 approaches. First one is a marker-based enrichment method identifying the key genes potentially impacting myocytes in atrial fibrillation 8/n

A module-level GWAS enrichment method revealed transcriptional programs linked to 6 phenotype groups, including a module shared by Schwann cells, neurons, ICCs and neuroendocrine enriched w/ GWAS-nominated genes of psychiatric and cognitive traits 9/n

Gene expression (counts matrices) and metadata are available @gtexportal, sequence data @useAnVIL (requires dbGaP access to GTEx), and code for analyses and figures at github.com/broadinstitute… 10/n

Preprint is available on bioRxiv: biorxiv.org/content/10.110… 11/n

Please also check out other related studies from Quake lab @czbiohub (Tabula sapiens, tabula-sapiens-portal.ds.czbiohub.org) and Teichmann lab (Conde et al. doi.org/10.1101/2021.0…) 12/12

Last but not least I'd like to hugely thank amazing Leslie Gaffney and @GraphicAnja for beautiful graphics.

I am beyond grateful to have worked with the GTEx team, all Regev lab and Segre lab members and all others 🤓