Epigenetic Characterization of the Growth Hormone Gene Identifies SmcHD1 As a Regulator of Autosomal Gene Clusters

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2014 May 14

PMID 24818964

Citations 15

Authors

Shabnam Massah

Robert Hollebakken

Mark P Labrecque

Addie M Kolybaba

Timothy V Beischlag

Gratien G Prefontaine

Affiliations

Soon will be listed here.

Abstract

Regulatory elements for the mouse growth hormone (GH) gene are located distally in a putative locus control region (LCR) in addition to key elements in the promoter proximal region. The role of promoter DNA methylation for GH gene regulation is not well understood. Pit-1 is a POU transcription factor required for normal pituitary development and obligatory for GH gene expression. In mammals, Pit-1 mutations eliminate GH production resulting in a dwarf phenotype. In this study, dwarf mice illustrated that Pit-1 function was obligatory for GH promoter hypomethylation. By monitoring promoter methylation levels during developmental GH expression we found that the GH promoter became hypomethylated coincident with gene expression. We identified a promoter differentially methylated region (DMR) that was used to characterize a methylation-dependent DNA binding activity. Upon DNA affinity purification using the DMR and nuclear extracts, we identified structural maintenance of chromosomes hinge domain containing -1 (SmcHD1). To better understand the role of SmcHD1 in genome-wide gene expression, we performed microarray analysis and compared changes in gene expression upon reduced levels of SmcHD1 in human cells. Knock-down of SmcHD1 in human embryonic kidney (HEK293) cells revealed a disproportionate number of up-regulated genes were located on the X-chromosome, but also suggested regulation of genes on non-sex chromosomes. Among those, we identified several genes located in the protocadherin β cluster. In addition, we found that imprinted genes in the H19/Igf2 cluster associated with Beckwith-Wiedemann and Silver-Russell syndromes (BWS & SRS) were dysregulated. For the first time using human cells, we showed that SmcHD1 is an important regulator of imprinted and clustered genes.

Citing Articles

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In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype.

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Autosomal sex-associated co-methylated regions predict biological sex from DNA methylation.

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The effects of the DNA Demethylating reagent, 5-azacytidine on SMCHD1 genomic localization.

Massah S, Jubene J, Lee F, Beischlag T, Prefontaine G BMC Genet. 2020; 21(1):3.

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