Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways

Kheirallah, Alexander K.; de Moor, Cornelia H.; Faiz, Alen; Sayers, Ian; Hall, Ian P.

Abstract

BACKGROUND: Genetic studies of human lung function and Chronic Obstructive Pulmonary Disease have identified a highly significant and reproducible signal on 4q24. It remains unclear which of the two candidate genes within this locus may regulate lung function: GSTCD, a gene with unknown function, and/or INTS12, a member of the Integrator Complex which is currently thought to mediate 3'end processing of small nuclear RNAs.RESULTS: We found that, in lung tissue, 4q24 polymorphisms associated with lung function correlate with INTS12 but not neighbouring GSTCD expression. In contrast to the previous reports in other species, we only observed a minor alteration of snRNA processing following INTS12 depletion. RNAseq analysis of knockdown cells instead revealed dysregulation of a core subset of genes relevant to airway biology and a robust downregulation of protein synthesis pathways. Consistent with this, protein translation was decreased in INTS12 knockdown cells. In addition, ChIPseq experiments demonstrated INTS12 binding throughout the genome, which was enriched in transcriptionally active regions. Finally, we defined the INTS12 regulome which includes genes belonging to the protein synthesis pathways.CONCLUSION: INTS12 has functions beyond the canonical snRNA processing. We show that it regulates translation by regulating the expression of genes belonging to protein synthesis pathways. This study provides a detailed analysis of INTS12 activities on a genome-wide scale and contributes to the biology behind the genetic association for lung function at 4q24.

Citation

Kheirallah, A. K., de Moor, C. H., Faiz, A., Sayers, I., & Hall, I. P. (2017). Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways. BMC Genomics, 18(1), Article 248. https://doi.org/10.1186/s12864-017-3628-3

• Journal Article Type: Article
• Acceptance Date: Mar 14, 2017
• Online Publication Date: Mar 23, 2017
• Publication Date: Mar 23, 2017
• Deposit Date: Mar 29, 2017
• Publicly Available Date: Mar 29, 2017
• Journal: BMC Genomics
• Electronic ISSN: 1471-2164
• Publisher: Springer Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 18
• Issue: 1
• Article Number: 248
• DOI: https://doi.org/10.1186/s12864-017-3628-3
• Keywords: Integrator Complex, INTS12, snRNA processing, Protein synthesis, Regulation of gene expression, Pathway dysregulation, Histone modification, Accessible chromatin, Transcription
• Public URL: https://nottingham-repository.worktribe.com/output/851685
• Publisher URL: http://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-3628-3
• Contract Date: Mar 29, 2017