GCM2 Silencing in Parathyroid Adenoma Is Associated With Promoter Hypermethylation and Gain of Methylation on Histone 3.
Adenoma
/ genetics
Adult
Case-Control Studies
Cell Line, Tumor
DNA Methylation
/ genetics
Epigenesis, Genetic
/ genetics
Female
Gene Silencing
Histones
/ genetics
Humans
Male
Middle Aged
Nuclear Proteins
/ genetics
Parathyroid Glands
/ metabolism
Parathyroid Neoplasms
/ genetics
Promoter Regions, Genetic
/ genetics
RNA, Messenger
/ metabolism
Transcription Factors
/ genetics
5-aza-2′-deoxycytidine
chromatin immunoprecipitation
glial cells missing 2
histone methylation
primary hyperparathyroidism
promoter hypermethylation
Journal
The Journal of clinical endocrinology and metabolism
ISSN: 1945-7197
Titre abrégé: J Clin Endocrinol Metab
Pays: United States
ID NLM: 0375362
Informations de publication
Date de publication:
27 09 2021
27 09 2021
Historique:
received:
10
09
2020
pubmed:
3
6
2021
medline:
17
11
2021
entrez:
2
6
2021
Statut:
ppublish
Résumé
Glial cells missing 2 (GCM2), a zinc finger-transcription factor, is essentially required for the development of the parathyroid glands. We sought to identify whether the epigenetic alterations in GCM2 transcription are involved in the pathogenesis of sporadic parathyroid adenoma. In addition, we examined the association between promoter methylation and histone modifications with disease indices. Messenger RNA (mRNA) and protein expression of GCM2 were analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry in 33 adenomatous and 10 control parathyroid tissues. DNA methylation and histone methylation/acetylation of the GCM2 promoter were measured by bisulfite sequencing and chromatin immunoprecipitation-qPCR. Additionally, we investigated the role of epigenetic modifications on GCM2 and DNA methyltransferase 1 (DNMT1) expression in parathyroid (PTH)-C1 cells by treating with 5-aza-2'-deoxycytidine (DAC) and BRD4770 and assessed for GCM2 mRNA and DNMT1 protein levels. mRNA and protein expression of GCM2 were lower in sporadic adenomatous than in control parathyroid tissues. This reduction correlated with hypermethylation (P < .001) and higher H3K9me3 levels in the GCM2 promoter (P < .04) in adenomas. In PTH-C1 cells, DAC treatment resulted in increased GCM2 transcription and decreased DNMT1 protein expression, while cells treated with the BRD4770 showed reduced H3K9me3 levels but a nonsignificant change in GCM2 transcription. These findings suggest the concurrent association of promoter hypermethylation and higher H3K9me3 with the repression of GCM2 expression in parathyroid adenomas. Treatment with DAC restored GCM2 expression in PTH-C1 cells. Our results showed a possible epigenetic landscape in the tumorigenesis of parathyroid adenoma and also that DAC may be a promising avenue of research for parathyroid adenoma therapeutics.
Identifiants
pubmed: 34077544
pii: 6291069
doi: 10.1210/clinem/dgab374
pmc: PMC8475237
doi:
Substances chimiques
GCM2 protein, human
0
Histones
0
Nuclear Proteins
0
RNA, Messenger
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e4084-e4096Subventions
Organisme : NIH HHS
ID : DK43858
Pays : United States
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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