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

Kheirallah, AK; de Moor, CH; Faiz, A; Sayers, I; Hall, IP

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

Kheirallah, AK de Moor, CH Faiz, A

Sayers, I Hall, IP

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Publication Type:: Journal Article
Citation:: BMC genomics, 2017, 18 (1), pp. 248 - ?
Issue Date:: 2017-03-23

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Field	Value	Language
dc.contributor.author	Kheirallah, AK	en_US
dc.contributor.author	de Moor, CH	en_US
dc.contributor.author	Faiz, A https://orcid.org/0000-0003-1740-3538	en_US
dc.contributor.author	Sayers, I	en_US
dc.contributor.author	Hall, IP	en_US
dc.date.available	2017-03-14	en_US
dc.date.issued	2017-03-23	en_US
dc.identifier.citation	BMC genomics, 2017, 18 (1), pp. 248 - ?	en_US
dc.identifier.uri	http://hdl.handle.net/10453/128093
dc.description.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.	en_US
dc.relation.ispartof	BMC genomics	en_US
dc.relation.isbasedon	10.1186/s12864-017-3628-3	en_US
dc.subject.classification	Bioinformatics	en_US
dc.subject.mesh	Lung	en_US
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Carrier Proteins	en_US
dc.subject.mesh	RNA, Small Nuclear	en_US
dc.subject.mesh	Protein Biosynthesis	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Polymorphism, Single Nucleotide	en_US
dc.subject.mesh	Alleles	en_US
dc.subject.mesh	Quantitative Trait Loci	en_US
dc.subject.mesh	Gene Knockdown Techniques	en_US
dc.subject.mesh	Intracellular Signaling Peptides and Proteins	en_US
dc.title	Lung function associated gene Integrator Complex subunit 12 regulates protein synthesis pathways	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	18	en_US
utslib.for	06 Biological Sciences	en_US
utslib.for	08 Information and Computing Sciences	en_US
utslib.for	11 Medical and Health Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	18	en_US

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.

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http://hdl.handle.net/10453/128093