Epigenomic silencing of the BMP-4 gene in pituitary adenomas: a potential target for epidrug-induced re-expression.
Bone morphogenetic protein (BMP)-4 is a key mediator of anterior pituitary organogenesis. However, through inappropriate expression patterns, BMP-4 is also pathogenic in a pituitary adenoma subtype-specific context. In these cases, increase or decrease in BMP-4 in lactotroph- and corticotroph-derived adenomas, respectively, is consistent with a bifunction role for this protein toward either promotion or inhibition of cell proliferation and hormone secretion. To gain insight into the aberrations responsible for differential expression, we examined BMP-4 transcript and protein expression patterns in the major adenomas subtypes. BMP-4 transcript and protein are differentially expressed and show increase in the majority of prolactinomas relative to normal pituitary, whereas the majority of other adenoma subtypes show reduced expression relative to both prolactinoma and normal pituitaries. Reduced expression of BMP-4 is not associated with change in CpG island methylation status. However, histone tail modifications are apparent, as enrichment for a modification associated with silent genes, H3K27me3, and depletion of a modification associated with active genes, H3K9Ac. In pituitary cell lines, reduced BMP-4 expression is also associated with similar histone tail modifications and contemporaneous increase in CpG island methylation. In these cells, coincubation with the demethylating agent zebularine and histone deacetylase inhibitor, trichostatin A, reversed epigenetic changes and restored expression of BMP-4. These studies show that, in contrast to prolactinomas, other adenoma subtypes show reduced expression of BMP-4 where epidrug induced reexpression, alone or in combination with conventional therapies, may offer new treatment strategies.
Human Disease and Genomics Group, Institute of Science and Technology in Medicine, School of Medicine, Keele University, Stoke on Trent, Staffordshire ST4 7QB, United Kingdom.
Kiren
K
Yacqub-Usman
Cuong V
CV
Duong
Richard N
RN
Clayton
William E
WE
Farrell
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D003562:Cytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D044127:Epigenesis, Genetic / Q000235:genetics*; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D010911:Pituitary Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D055415:Bone Morphogenetic Protein 4; D006657:Histones; D003562:Cytidine; C009131:pyrimidin-2-one beta-ribofuranoside