title: Cubilin expression is monoallelic and epigenetically augmented via PPARs.
abstract: BACKGROUND
  Cubilin is an endocytic receptor that is necessary for renal and intestinal absorption of a range of ligands. Endocytosis mediated by cubilin and its co-receptor megalin is the principal mechanism for proximal tubule reabsorption of proteins from the glomerular filtrate. Cubilin is also required for intestinal endocytosis of intrinsic factor-vitamin B12 complex. Despite its importance, little is known about the regulation of cubilin expression.
  
  
  RESULTS
  Here we show that cubilin expression is under epigenetic regulation by at least two processes. The first process involves inactivation of expression of one of the cubilin alleles. This monoallelic expression state could not be transformed to biallelic by inhibiting DNA methylation or histone deacetylation. The second process involves transcriptional regulation of cubilin by peroxisome proliferator-activated receptor (PPAR) transcription factors that are themselves regulated by DNA methylation and histone deacetylation. This is supported by findings that inhibitors of DNA methylation and histone deacetylation, 5Aza and TSA, increase cubilin mRNA and protein in renal and intestinal cell lines. Not only was the expression of PPARα and γ inducible by 5Aza and TSA, but the positive effects of TSA and 5Aza on cubilin expression were also dependent on both increased PPAR transcription and activation. Additionally, 5Aza and TSA had similar effects on the expression of the cubilin co-receptor, megalin.
  
  
  CONCLUSIONS
  Together, these findings reveal that cubilin and megalin mRNA expression is under epigenetic control and thus point to new avenues for overcoming pathological suppression of these genes through targeting of epigenetic regulatory processes.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Obaidullah
authors.initials: O
authors.lastname: Aseem
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Barth
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Klatt
authors.forename: Brian T
authors.initials: BT
authors.lastname: Smith
authors.forename: W Scott
authors.initials: WS
authors.lastname: Argraves
mesh_terms: D000418:Albumins / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001374:Azacitidine / Q000494:pharmacology; D001483:Base Sequence; D018938:Caco-2 Cells; D044127:Epigenesis, Genetic / Q000187:drug effects; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007422:Intestines / Q000166:cytology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics*
chemical_list: D000418:Albumins; C424167:Amn protein, mouse; D006877:Hydroxamic Acids; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D008565:Membrane Proteins; D047492:Peroxisome Proliferator-Activated Receptors; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor; C012589:trichostatin A; D001374:Azacitidine