INTS1 is required for maintaining accurate transcriptional integrity and behavior in zebrafish

Precise regulation of RNA polymerase II (RNAPII) is fundamental to transcriptional fidelity in eukaryotes. The Integrator complex, a conserved multi-subunit assembly, safeguards transcriptional integrity through its interaction with RNAPII, mediating transcription initiation and termination by nascent RNA cleavage and 3′ end processing. INTS1, the largest subunit of the Integrator complex, is critical for its function, and its mutations are linked to human neurodevelopmental disorders, yet the underlying transcriptional effects remain poorly defined. Here, we characterize the global transcriptional effects of INTS1 deficiency in zebrafish. INTS1 loss leads to widespread gene expression changes, including genes linked to hyperactivity and pathways associated with attention-deficit/hyperactivity disorder. We observe mutant-specific first intron retentions and transcript extensions. These findings underscore a central role for INTS1 in coordinating transcriptional regulation and highlight the essential function of the Integrator complex in maintaining transcriptome integrity. Together, they offer insights into how INTS1 disruption may contribute to behavioral and physiological abnormalities.