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BMC Genomics

, 18:248

Human and rodent genomics

Abstract

BackgroundGenetic 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.

ResultsWe 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.

ConclusionINTS12 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.

KeywordsIntegrator Complex INTS12 snRNA processing Protein synthesis Regulation of gene expression Pathway dysregulation Histone modification Accessible chromatin Transcription AbbreviationsASNSAsparagine Synthetase

ATF4Activating transcription factor 4

ChIPseqChromatin immunoprecipitation and sequencing

cis-eQTLNearby expression quantitative trait locus

COPDChronic Obstructive Pulmonary Disease

CPMCounts per methionine

CTCFCCCTC-binding factor

D-siRNADicer substrate small interfering RNA

eQTLExpression quantitative trait locus

GARSGlycyl-tRNA synthetase

GSEAGene set enrichment analysis

GSTCDGlutathione S-transferase, C-terminal Domain Containing

GWASGenome-wide association studies

H3K27me3Histone 3 lysine 27 trimethylation

H3K36me3Histone 3 lysine 36 trimethylation

H3K4me3Histone 3 lysine 4 trimethylation

HBECHuman bronchial epithelial cell

IL1R1Interleukin 1 receptor 1

INTS12Integrator Complex subunit 12

INTScomIntegrator Complex

LEPLeptin

lincRNALong intergenic RNA

MARSMethionyl-tRNA synthetase

PHDPlant homeodomain

POLIIRNA polymerase II

qPCRQuantitative polymerase chain reaction

RNAiRNA interference

RNAseqRNA sequencing

SERPINA1α1-antitrypsin

snoRNASmall nucleolar RNA

SNPSingle nucleotide polymorphism

snRNASmall nuclear RNA

TESTransactional end site

TGFβITransforming growth factor β 1

trans-eQTLDistant eQTL

TSSTranscriptional start site

Electronic supplementary materialThe online version of this article doi:10.1186-s12864-017-3628-3 contains supplementary material, which is available to authorized users.

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Author: Alexander K. Kheirallah - Cornelia H. de Moor - Alen Faiz - Ian Sayers - Ian P. Hall

Source: https://link.springer.com/







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