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... - ThreadSky

kaiamattioli.bsky.social • 69 days ago

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

https://www.sciencedirect.com/science/article/abs/pii/S1097276525001972

Comments

anush-chp.bsky.social•69 days ago

Congratulations Kaia!!

kaiamattioli.bsky.social•69 days ago

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)

kaiamattioli.bsky.social•69 days ago

in RNA-seq data, TFs commonly exhibit quantitative "shifts" in isoform expression across conditions, with a smaller fraction showing dramatic on/off "switch" events, particularly in developmental contexts

kaiamattioli.bsky.social•69 days ago

but how do TF isoforms differ in functions? we generated a collection of 693 TF isoforms across 246 human TF genes & profiled them across three primary TF "molecular activities": DNA binding, protein binding, and transcriptional activation/repression

kaiamattioli.bsky.social•69 days ago

TF isoforms with altered DBDs fail to bind DNA (as expected). but isoforms with identical DBDs often show differential DNA binding, supporting the reported importance of IDRs in DNA binding, & highlighting the difficulty of predicting function from sequence alone

kaiamattioli.bsky.social•69 days ago

TF isoforms also differ in their ability to activate/repress transcription, and this differential activity is associated with differences in interactions with cofactors and signaling partners. once again, predicting these changes from sequence alone is very difficult (a theme)!

kaiamattioli.bsky.social•69 days ago

TF paralogs have long been appreciated to add complexity to gene regulatory networks. after controlling for differences in amino acid sequence identity, we see that TF isoforms can be as functionally distinct from each other as TF paralogs

hsnajafabadi.bsky.social•68 days ago

Really nice work! Congrats!

martinbjensen.bsky.social•68 days ago

Very nice

kaiamattioli.bsky.social•68 days ago

thank you!

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