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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.

Authors

Alexander K. Kheirallah

Cornelia H. de Moor

Alen Faiz

Ian Sayers

Ian P. Hall



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.

Journal Article Type Article
Publication Date 2017-12
Journal BMC Genomics
Electronic ISSN 1471-2164
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 18
Issue 1
APA6 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), https://doi.org/10.1186/s12864-017-3628-3
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
Publisher URL http://bmcgenomics.biomedcentral.com/articles/10.1186/s12864-017-3628-3
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0


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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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