Dave Shechner

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

This work was spearheaded by Evan Kania (from my lab) and Sara Bianchi (from @berterolab.bsky.social), as part of a close collaboration with Chuck Murry's lab. But in truth, this was a tremendous effort from many talented colleagues and friends, whom I'm honored to know.

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

And it suggests a number of big questions that we're excited to continue pursuing. How many other mRNA-scaffolded "factories" are there? Do they share the same molecular and regulatory architecture? Does dysregulation of these nuclear-architectural mRNAs drive disease?

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

QKI and SAFB recruitment required both RBM20 and TTN RNA, but not each other—evoking a scaffold-client model seen in other nuclear bodies. Intriguingly, SAFB knockdown opposed the effects of RBM20 loss on many TID-localized genes' expression. Maybe these factors act in opposition?

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

Finally, we used O-MAP to probe the TTN factory proteome. This remarkable compartment appears to integrate RNA biogenesis with chromatin compartmentalization, recruiting tons of exciting chromatin regulators (cohesin; SAFB) and RBPs (QKI; SRSFs; ELAVL1).

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

We hypothesized that the "denuded" TTN transcript might be partly to blame, aberrantly binding RBPs and sequestering them from their normal targets. This inspired a bonkers experiment: if our model's true, removing the TTN RNA should rescue some splicing defects in ∆RBM20 cells?!

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

We next characterized the TTN factory transcriptome, revealing hundreds of RNAs that specifically localize near nascent TTN in WT and ∆RBM20 cells. Almost none of these RNAs are encoded in TTN-proximal DNA loci, suggesting that they're localized post-transcriptionally.

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

We began by probing the factory's genomic interactions, which revealed a hub of Mb-scale, TTN-interacting chromatin domains in both cis (CIDs) and trans (TIDs). Strikingly, in ∆RBM20 cells, these TTN RNA–chromatin contacts completely disappear!

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

This approach yielded exceptionally precise biotinylation in both WT and ∆RBM20 cardiomyocytes: just two biotin foci—corresponding to the two alleles of TTN. In the context of two meters of folded DNA, O-MAP can home in and affinity-tag a single-locus nuclear compartment.

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

So what's inside the TTN RNA factory, and how is this molecular architecture remodeled by loss of RBM20? We realized we could ask this question using our O-MAP technology—a nearly universal method for RNA-targeted microenvironment-mapping: tinyurl.com/58xcrxas

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

In 2019, @berterolab.bsky.social, Fields et al. discovered an mRNA that appears to do just this. In cardiomyocytes, nascent TTN RNA organizes a compartment that concentrates the splicing factor RBM20 and brings together loci from multiple chromosomes. An "RNA Factory" scaffolded on a pre-mRNA!

New (to you?) preprint alert! Can protein-coding mRNAs "moonlight" as nuclear-architectural RNAs? 🧬 Our revised preprint uncovers how nascent TTN RNA organizes a specialized nuclear compartment in cardiac cells—and how its disruption may contribute to heart disease. A thread! 🧵👇

Aw, yeah! It’s en-dash time, people!

Just updated my phone OS, and apparently the calendar doubles as a karyotype now?

Just updated my phone OS, and apparently the calendar doubles as a karyotype now?