Dataset Information

Tandem repeats of the 5' flanking region of human MUC5AC have a role as a novel enhancer in MUC5AC gene expression.

ABSTRACT: MUC5AC is a well-known gastric differentiation marker, which has been frequently used for the classification of stomach cancer. However, the molecular mechanism of regulation of MUC5AC expression remains to be elucidated. In previous studies, we have shown that Gli regulated MUC5AC transcription through the Gli-binding motif in the 5' region of MUC5AC. Gli played important roles, but independently was not sufficient for MUC5AC expression. In this study, we analyzed a 4010 bp fragment of the 5'-flanking promoter region of the human MUC5AC gene by luciferase assay, and found a novel distal enhancer region located between -1434 bp to -3000 bp upstream from the first ATG initiation codon. This region is composed of repetitive DNA sequences 5'-TCACTCAC-3'. The strength of enhancer activities depended on the length of the repetitive region. The tandem repeats are conserved among primates, but not in other mammals. The tandem repeat regions enhanced promoter activities not only of MUC5AC but also of other genes. The enhancer effect of the tandem repeat regions was maintained even when inverted. ChIP analysis revealed that H3K9me3 binds to the tandem repeat regions. Together, our results suggest that the tandem repeat region in the MUC5AC promoter has the potential to act as a strong enhancer, and H3K9me3 may contribute to histone modifications of this region.

SUBMITTER: Kageyama-Yahara N

PROVIDER: S-EPMC6449733 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Tandem repeats of the 5' flanking region of human MUC5AC have a role as a novel enhancer in MUC5AC gene expression.

Kageyama-Yahara Natsuko N Yamamichi Nobutake N Takahashi Yu Y Takeuchi Chihiro C Matsumoto Yuta Y Sakaguchi Yoshiki Y Koike Kazuhiko K

Biochemistry and biophysics reports 20190404

MUC5AC is a well-known gastric differentiation marker, which has been frequently used for the classification of stomach cancer. However, the molecular mechanism of regulation of MUC5AC expression remains to be elucidated. In previous studies, we have shown that Gli regulated MUC5AC transcription through the Gli-binding motif in the 5' region of MUC5AC. Gli played important roles, but independently was not sufficient for MUC5AC expression. In this study, we anal ...[more]

PMID: 30993217

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Project description:BackgroundCardiomyopathy is a clinically and genetically heterogeneous heart condition that can lead to heart failure and sudden cardiac death in childhood. While it has a strong genetic basis, the genetic aetiology for over 50% of cardiomyopathy cases remains unknown.MethodsIn this study, we analyse the characteristics of tandem repeats from genome sequence data of unrelated individuals diagnosed with cardiomyopathy from Canada and the United Kingdom (n = 1216) and compare them to those found in the general population. We perform burden analysis to identify genomic and epigenomic features that are impacted by rare tandem repeat expansions (TREs), and enrichment analysis to identify functional pathways that are involved in the TRE-associated genes in cardiomyopathy. We use Oxford Nanopore targeted long-read sequencing to validate repeat size and methylation status of one of the most recurrent TREs. We also compare the TRE-associated genes to those that are dysregulated in the heart tissues of individuals with cardiomyopathy.FindingsWe demonstrate that tandem repeats that are rarely expanded in the general population are predominantly expanded in cardiomyopathy. We find that rare TREs are disproportionately present in constrained genes near transcriptional start sites, have high GC content, and frequently overlap active enhancer H3K27ac marks, where expansion-related DNA methylation may reduce gene expression. We demonstrate the gene silencing effect of expanded CGG tandem repeats in DIP2B through promoter hypermethylation. We show that the enhancer-associated loci are found in genes that are highly expressed in human cardiomyocytes and are differentially expressed in the left ventricle of the heart in individuals with cardiomyopathy.InterpretationOur findings highlight the underrecognized contribution of rare tandem repeat expansions to the risk of cardiomyopathy and suggest that rare TREs contribute to ∼4% of cardiomyopathy risk.FundingGovernment of Ontario (RKCY), The Canadian Institutes of Health Research PJT 175329 (RKCY), The Azrieli Foundation (RKCY), SickKids Catalyst Scholar in Genetics (RKCY), The University of Toronto McLaughlin Centre (RKCY, SM), Ted Rogers Centre for Heart Research (SM), Data Sciences Institute at the University of Toronto (SM), The Canadian Institutes of Health Research PJT 175034 (SM), The Canadian Institutes of Health Research ENP 161429 under the frame of ERA PerMed (SM, RL), Heart and Stroke Foundation of Ontario & Robert M Freedom Chair in Cardiovascular Science (SM), Bitove Family Professorship of Adult Congenital Heart Disease (EO), Canada Foundation for Innovation (SWS, JR), Canada Research Chair (PS), Genome Canada (PS, JR), The Canadian Institutes of Health Research (PS).

Dataset Information

Tandem repeats of the 5' flanking region of human MUC5AC have a role as a novel enhancer in MUC5AC gene expression.

Publications

Tandem repeats of the 5' flanking region of human <i>MUC5AC</i> have a role as a novel enhancer in <i>MUC5AC</i> gene expression.

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