Luke Lambourne

Excited to share this collaborative review with @dsegre.bsky.social and @devmoy.bsky.social. We discuss common issues with context-specific genome-scale metabolic network models and provide recommendation for future model development.

Exited to share our recent work on viral cis-regulatory elements in collaboration with @tewhey.bsky.social!
We identified >2000 CREs across the genomes of 27 human-infecting dsDNA viruses from the Herpesvirus, Adenovirus, Papillomavirus, and Polyomavirus families.
www.biorxiv.org/content/10.1...
1/8

Variant characterization in the intrinsically disordered human proteome Variant effect prediction remains a key challenge to resolve in precision medicine. Sophisticated computational models that exploit sequence conservation and structure are increasingly successful in t...

Variant characterization in the intrinsically disordered human proteome - here is how we did it using short linear motif prediction, AlphaFold, and experimentation. Check out our preprint: www.biorxiv.org/cgi/content/...

CoQ imbalance drives reverse electron transport to disrupt liver metabolism - Nature Reverse electron transport is the mechanism behind excess mitochondrial reactive oxygen species in the livers of obese mice, which has implications for developing therapeutics for fatty liver dis...

Congrats to Renata Goncalves who led a study in Gokhan Hotamisligil's lab that has just come out in Nature - ably assisted by Jillian Riveros!

www.nature.com/articles/s41...

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms Lambourne, Mattioli, Santoso, et al. compare protein isoforms of the same transcription factor genes through high-throughput profiling of DNA-binding, protein-binding, activation, localization, and condensate formation. Differences between isoforms are widespread, often unpredictable from sequence differences, and inform a disease-associated categorization of alternative isoforms into rewirers or negative regulators.

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms Lambourne, Mattioli, Santoso, et al. compare protein isoforms of the same transcription factor genes through high-throughput profiling of DNA-binding, protein-binding, activation, localization, and condensate formation. Differences between isoforms are widespread, often unpredictable from sequence differences, and inform a disease-associated categorization of alternative isoforms into rewirers or negative regulators.

Online Now: Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms Online now:

reposting the 🧵 from the other site that I wrote when the preprint came out:

TFs, like most genes, are frequently expressed as a series of multiple distinct isoforms. these isoforms (by definition) differ in sequence -- often in annotated protein domain regions (e.g. DNA-binding & effector domains)

The project was a huge multi-lab collaboration over several years. Thanks to @kaiamattioli.bsky.social @fuxmanlab.bsky.social @nathansalomonis.bsky.social @annaber.bsky.social @alexholehouse.bsky.social @mcalderwood.bsky.social and all the other authors not on bluesky!

We've added a few things since the preprint: biophysical modeling of how differences between disordered regions can affect DNA binding, a deeper look at how the differences in molecular function between isoforms relate to differential isoform expression in cancer and development.

We found that:
- 2/3 of alternative isoforms showed some difference from the reference
- These differences were often unpredictable from the aa sequence differences alone
- alt isoforms fell into two categories: Negative Regulators, and Rewirers

Data is browsable at: TFisoDB.org

The published version of our transcription factor isoforms survey is online

www.sciencedirect.com/science/arti...

we cloned 100's of isoforms (that arise through alternative splicing etc.) testing them in high-throughput assays for DNA-binding, protein-binding, activation, and more.

our work on the molecular differences between transcription factor isoforms is out now in Molecular Cell!

key point: 2/3rds of TF isos differ in properties like DNA binding & transcriptional activity

many are "negative regulators" & misexpressed in cancer

www.sciencedirect.com/science/arti...

Foreword to "The Measles Book", written by RFK, Jr. promises that "readers--Americans and global consumers of measles vaccines--will learn that they have been misled by the pharmaceutical industry and their captured government agency allies into believing that measles is a deadly disease and that measles vaccines are necessary, safe, and effective."

As the first measles death in the US since 2015--an unvaccinated child--is reported, let us read the thoughts of our new Secretary of Health and Human Services on this disease. www.reuters.com/world/us/fir... (Foreword to "The Measles Book", 2021)

On Wednesday 2/26, I’ll be in Boston to give a Harvard Science Book Talk. I’ll have a marvelous relic of aerobiological history to unveil. Details here: www.harvard.com/event/carl-z... 3/5

The STARLING has landed - excited to share new work from @bornanovak.bsky.social and @jefflotthammer.bsky.social in what is also Borna's first Bluesky post!

If you're at BPS, I'll be speaking about this this afternoon in IDP SG, and Borna and Jeff both have posters (Sunday B112 and Wed B152).

Interested in learning about biases in protein-protein interface predictions with AlphaFold2? Check out our new review on this topic:

authors.elsevier.com/a/1kbSa_,2Bd...

Btw, the abstract deadline has been extended to Jan 27!

🧪 If you are a network (or network-curious!) biologist, please consider attending the upcoming CSHL Network Biology Meeting. Details + abstract deadline below!

A pharmacological chaperone stabilizer rescues the expression of the vast majority of pathogenic variants in a G protein-coupled receptor Reduced protein stability is the most frequent mechanism by which rare missense variants cause disease. A promising therapeutic avenue for treating destabilizing variants is pharmacological chaperones...

Can a single small molecule rescue the stability of nearly all mutations in a protein?
Our new preprint by Taylor Mighell
www.biorxiv.org/content/10.1...
thread on the other place: x.com/taylor_mighe...