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Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells

Kitchen, Mark O.; Yacub-Usman, Kiren; Emes, Richard D.; Richardson, Alan; Clayton, Richard N.; Farrell, William E.

Authors

Mark O. Kitchen

Kiren Yacub-Usman

RICHARD EMES richard.emes@nottingham.ac.uk
Professor of Bioinformatics

Alan Richardson

Richard N. Clayton

William E. Farrell



Abstract

Transgenic mice overexpressing the high mobility group A (HMGA) genes, Hmga1 or Hmga2 develop pituitary tumours and their overexpression is also a frequent finding in human pituitary adenomas. In some cases, increased expression of HMGA2 but not that of HMGA1 is consequent to genetic perturbations. However, recent studies show that down-regulation of microRNA (miRNA), that contemporaneously target the HMGA1 and HMGA2 transcripts, are associated with their overexpression. In a cohort of primary pituitary adenoma we determine the impact of epigenetic modifications on the expression of HMGA-targeting miRNA. For these miRNAs, chromatin immunoprecipitations showed that transcript down-regulation is correlated with histone tail modifications associated with condensed silenced genes. The functional impact of epigenetic modification on miRNA expression was determined in the rodent pituitary cell line, GH3. In these cells, histone tail, miRNA-associated, modifications were similar to those apparent in human adenoma and likely account for their repression. Indeed, challenge of GH3 cells with the epidrugs, zebularine and TSA, led to enrichment of the histone modification, H3K9Ac, associated with active genes, and depletion of the modification, H3K27me3, associated with silent genes and re-expression of HMGA-targeting miRNA. Moreover, epidrugs challenges were also associated with a concomitant decrease in hmga1 transcript and protein levels and concurrent increase in bmp-4 expression. These findings show that the inverse relationship between HMGA expression and targeting miRNA is reversible through epidrug interventions. In addition to showing a mechanistic link between epigenetic modifications and miRNA expression these findings underscore their potential as therapeutic targets in this and other diseases.

Citation

Kitchen, M. O., Yacub-Usman, K., Emes, R. D., Richardson, A., Clayton, R. N., & Farrell, W. E. (2015). Epidrug mediated re-expression of miRNA targeting the HMGA transcripts in pituitary cells. Pituitary, 18(5), 674-684. https://doi.org/10.1007/s11102-014-0630-5

Journal Article Type Article
Acceptance Date Jan 4, 2015
Online Publication Date Jan 4, 2015
Publication Date 2015-10
Deposit Date Dec 18, 2015
Publicly Available Date Dec 18, 2015
Journal Pituitary
Print ISSN 1386-341X
Electronic ISSN 1573-7403
Publisher Springer Verlag
Peer Reviewed Peer Reviewed
Volume 18
Issue 5
Pages 674-684
DOI https://doi.org/10.1007/s11102-014-0630-5
Keywords pituitary, microRNA, chromatin, epidrugs, HMGA1
Public URL http://eprints.nottingham.ac.uk/id/eprint/31143
Publisher URL http://link.springer.com/article/10.1007/s11102-014-0630-5
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
Additional Information This is a post-peer-review, pre-copyedit version of an article published in Pituitary. The final authenticated version is available online at: http://dx.doi.org/10.1007/s11102-014-0630-5

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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