Language

English

Publication Date

4-3-2025

Journal

Molecular Cell

DOI

10.1016/j.molcel.2025.03.004

PMID

40147441

PMCID

PMC12121496

PubMedCentral® Posted Date

4-3-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Most human transcription factor (TF) genes encode multiple protein isoforms differing in DNA-binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators," both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.

Keywords

Humans, Protein Isoforms, Transcription Factors, Gene Regulatory Networks, Protein Binding, Transcriptional Activation, Neoplasms, Alternative Splicing

Published Open-Access

yes

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