Aberrant Epigenetic Alteration of <i>PAX1</i> Expression Contributes to Parathyroid Tumorigenesis

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Abstract

Context

Primary hyperparathyroidism (PHPT) results from the hypersecretion of parathyroid hormone from parathyroid tumors. A transcription factor, namely Paired box1 (PAX1), is active in parathyroid gland development.

Objective

We aimed to study potential epigenetic-mediated mechanism of PAX1 gene in sporadic parathyroid adenomas.

Methods

In parathyroid adenomas tissues, we analyzed the DNA methylation via bisulfite-specific polymerase chain reaction (BSP) and histone modifications via chromatin immunoprecipitation in regulating the differential expression of PAX1.

Results

The results showed that mRNA and protein expression of PAX1 was significantly reduced in parathyroid adenomas. Bisulfite sequencing demonstrated hypermethylation in the promoter region of PAX1 (35%; 14/40) and lower levels of histone 3 lysine 9 acetylation (H3K9ac) were observed on the promoter region of PAX1 (6-fold; P < .004) in parathyroid adenomas. Furthermore, upon treatment with a pharmacologic inhibitor, namely 5′aza-2 deoxycytidine, in rat parathyroid continuous cells, we found re-expression of PAX1 gene.

Conclusion

Our study not only reveals expression of PAX1 is epigenetically deregulated but also paves a way for clinical and therapeutic implications in patients with PHPT.

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Most cited references 28

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Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain.

Schahram Akbarian, Z. Chen, Rudolf Jaenisch … (2002)

The Mecp2 gene has been shown to be mutated in most cases of human Rett syndrome, and mouse models deleted for the ortholog have been generated. Lineage-specific deletion of the gene indicated that the Rett-like phenotype is caused by Mecp2 deficiency in neurons. Biochemical evidence suggests that Mecp2 acts as a global transcriptional repressor, predicting that mutant mice should have genome-wide transcriptional deregulation. We tested this hypothesis by comparing global gene expression in wild-type and Mecp2 mutant mice. The results of numerous microarray analyses revealed no dramatic changes in transcription even in mice displaying overt disease symptoms, although statistical power analyses of the data indicated that even a small number of relatively subtle changes in transcription would have been detected if present. However, a classifier consisting of a combined small set of genes was able to distinguish between mutant and wild-type samples with high accuracy. This result suggests that Mecp2 deficiency leads to subtle gene expression changes in mutant brains which may be associated with the phenotypic changes observed.

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DNA Methyltransferases: A Novel Target for Prevention and Therapy

Dharmalingam Subramaniam, Ravi Thombre, Animesh Dhar … (2014)

Cancer is the second leading cause of death in US. Despite the emergence of new, targeted agents, and the use of various therapeutic combinations, none of the available treatment options are curative in patients with advanced cancer. Epigenetic alterations are increasingly recognized as valuable targets for the development of cancer therapies. DNA methylation at the 5-position of cytosine, catalyzed by DNA methyltransferases (DNMTs), is the predominant epigenetic modification in mammals. DNMT1, the major enzyme responsible for maintenance of the DNA methylation pattern is located at the replication fork and methylates newly biosynthesized DNA. DNMT2 or TRDMT1, the smallest mammalian DNMT is believed to participate in the recognition of DNA damage, DNA recombination, and mutation repair. It is composed solely of the C-terminal domain, and does not possess the regulatory N-terminal region. The levels of DNMTs, especially those of DNMT3B, DNMT3A, and DNMT3L, are often increased in various cancer tissues and cell lines, which may partially account for the hypermethylation of promoter CpG-rich regions of tumor suppressor genes in a variety of malignancies. Moreover, it has been shown to function in self-renewal and maintenance of colon cancer stem cells and need to be studied in several cancers. Inhibition of DNMTs has demonstrated reduction in tumor formation in part through the increased expression of tumor suppressor genes. Hence, DNMTs can potentially be used as anti-cancer targets. Dietary phytochemicals also inhibit DNMTs and cancer stem cells; this represents a promising approach for the prevention and treatment of many cancers.

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Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis.

Matthew Oberley, Amy Weinmann, Tim Hui-Ming Huang … (2002)

Previously, identification of promoters regulated by mammalian transcription factors has relied upon overexpression studies. Here we present the identification of a large set of promoters that are bound by E2F in physiological conditions. Probing a human CpG microarray with chromatin immunoprecipitated using an antibody to E2F4, we have identified 68 unique target loci; 15% are bidirectional promoters and 25% recruit E2F via a mechanism distinct from the defined consensus site. Interestingly, although E2F has been shown previously to regulate genes involved in cell cycle progression, many of the new E2F target genes encode proteins involved in DNA repair or recombination. We suggest that human CpG microarrays, in combination with chromatin immunoprecipitation, will allow rapid identification of target promoters for many mammalian transcription factors.

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Author and article information

Contributors

Sanjay Kumar Bhadada: (View ORCID Profile)

Journal

Title: The Journal of Clinical Endocrinology & Metabolism

Publisher: The Endocrine Society

ISSN (Print): 0021-972X

ISSN (Electronic): 1945-7197

Publication date Created: February 01 2022

Publication date Created: January 18 2022

Publication date Created: August 28 2021

Publication date Other: February 01 2022

Publication date (Print): January 18 2022

Publication date (Electronic): August 28 2021

Volume: 107

Issue: 2

Pages: e783-e792

Affiliations

[1 ]Department of Endocrinology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

[2 ]Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

[3 ]Department of General Surgery, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

[4 ]Department of Biochemistry, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

[5 ]Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence 50121, Italy

[6 ]Bone and Mineral Research Laboratory, Henry Ford Hospital, Detroit, MI 48202, USA

Article

DOI: 10.1210/clinem/dgab626

PubMed ID: 34453169

SO-VID: 9181d2a4-a3cb-461b-bb1e-2dedb0d49249

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Aberrant Epigenetic Alteration of PAX1 Expression Contributes to Parathyroid Tumorigenesis

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Abstract

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Most cited references 28

Transcriptional profiling of a mouse model for Rett syndrome reveals subtle transcriptional changes in the brain.

DNA Methyltransferases: A Novel Target for Prevention and Therapy

Isolating human transcription factor targets by coupling chromatin immunoprecipitation and CpG island microarray analysis.

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