Research Summary: Loss of Integrator complex causes RNA Polymerase II to terminate prematurely, generating incomplete transcripts with retained introns. Intronic retroelements form immunogenic dsRNA that activates stress response in neurons, contributing to disease.
Author interview: Apoorva Baluapuri is a researcher at Harvard Medical School investigating transcriptional regulation mechanisms with focus on RNA Polymerase II and its implications in neurodevelopmental disorders and aging.
Lab: Karen Adelman, Harvard Medical School
What was the core problem you aimed to solve with this research?
I aimed to understand the mechanistic connection between mutations in the Integrator complex and human diseases, particularly neurodevelopmental disorders. While we knew that Integrator regulates RNA Polymerase II at gene promoters, it remained unclear how Integrator deficiency leads to disease symptoms. This research bridges the gap between the molecular function of Integrator and its role in maintaining cellular homeostasis.
How did you go about solving this problem?
We developed human cell lines with auxin-inducible degron tags on Integrator subunits, allowing us to rapidly deplete these proteins and study both immediate and long-term consequences. Using genomic approaches including transient transcriptome sequencing (TT-seq) and precision run-on sequencing (PRO-seq), we tracked transcriptional changes and identified where RNA Polymerase II was terminating prematurely. RNA immunoprecipitation coupled with sequencing (RIP-seq) helped us identify the origins of double-stranded RNA. We then validated our findings in patient-derived cells with Integrator mutations and demonstrated that correcting these mutations reversed the cellular phenotypes.
How would you explain your research outcomes (Key findings) to the non-scientific community?
We discovered that Integrator acts like a quality control checkpoint for gene expression. When this checkpoint is missing, immature RNA-producing machinery (RNA Polymerase II) escapes its normal controls and produces incomplete RNA transcripts. These incomplete transcripts contain retroelements like Alu sequences that can fold into abnormal double-stranded RNA structures. The cell recognizes these structures as threats (similar to viral infections) and triggers a stress response. In patients with Integrator mutations, this stress response becomes chronic and likely contributes to their neurological symptoms. Importantly, when we corrected the genetic mutation in patient cells, the double-stranded RNA accumulation and stress response diminished, suggesting potential therapeutic approaches.
“This work uncovers how transcription defects can trigger chronic stress signaling, connecting molecular mechanisms to neurological disease pathogenesis.” – Karen Adelman
What are the potential implications of your findings for the field and society?
Our findings establish a direct link between defective RNA production and disease mechanisms, particularly in neurodevelopmental disorders. We identified the integrated stress response as a potential therapeutic target for patients with Integrator mutations. Our work also reveals a previously unappreciated connection between RNA processing defects and innate immune sensing that may be relevant to other neurological conditions and aging-related diseases. More broadly, we’ve shown how cellular quality control mechanisms for RNA can be overwhelmed by abnormal transcription elongation, leading to severe consequences for cell health. This knowledge could guide the development of new therapeutics targeting RNA biogenesis or stress response pathways for multiple disorders.
What was the exciting moment during your research?
The most exciting moment was observing double-stranded RNA accumulation in neural progenitor cells derived from patients with INTS8 mutations. Seeing that correcting the genetic mutation significantly reduced dsRNA levels confirmed that our laboratory findings directly reflected disease pathology and suggested a potential avenue for therapeutic intervention. This moment connected years of molecular detective work to actual human disease, validating the physiological relevance of our discoveries and demonstrating that understanding fundamental mechanisms of gene expression can lead to insights into human disease.
Paper reference: Baluapuri, A., Zhao, N.C., Marina, R.J., Huang, K.L., Kuzkina, A., Amodeo, M.E., Stein, C.B., Ahn, L.Y., Farr, J.S., Schaffer, A.E., Khurana, V., Wagner, E.J., and Adelman, K. (2025). Integrator loss leads to dsRNA formation that triggers the integrated stress response. Cell 188, 1-18. https://doi.org/10.1016/j.cell.2025.03.025
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