Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control.
Mitochondrial ferritin (FtMt) is an iron storage protein belonging to the ferritin family but, unlike the cytosolic ferritin, it has an iron-unrelated restricted tissue expression. FtMt appears to be preferentially expressed in cell types characterized by high metabolic activity and oxygen consumption, suggesting a role in protecting mitochondria from iron-dependent oxidative damage. The human gene (FTMT) is intronless and its promoter region has not been described yet. To analyze the regulatory mechanisms controlling FTMT expression, we characterized the 5' flanking region upstream the transcriptional starting site of FTMT by in silico enquiry of sequences conservation, DNA deletion analysis, and ChIP assay. The data revealed a minimal promoter region and identified the presence of SP1, CREB and YY1 as positive regulators, and GATA2, FoxA1 and C/EBPβ as inhibitors of the transcriptional regulation. Furthermore, the FTMT transcription is increased by acetylating and de-methylating agent treatments in K562 and HeLa cells. These treatments up-regulate FtMt expression even in fibroblasts derived from a Friedreich ataxia patient, where it might exert a beneficial effect against mitochondrial oxidative damage. The expression of FTMT appears regulated by a complex mechanism involving epigenetic events and interplay between transcription factors.
San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milano, Italy.
Michela
M
Guaraldo
San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milano, Italy.
Paolo
P
Santambrogio
San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milano, Italy.
Elisabetta
E
Rovelli
University of Torino, Department of Clinical and Biological Sciences, AOU San Luigi Gonzaga, 10043 Orbassano, Torino, Italy.
Augusta
A
Di Savino
University of Torino, Department of Clinical and Biological Sciences, AOU San Luigi Gonzaga, 10043 Orbassano, Torino, Italy.
Giuseppe
G
Saglio
San Raffaele Scientific Institute, Center for Translational Genomics and Bioinformatics, 20132 Milano, Italy.
Davide
D
Cittaro
University of Torino, Department of Clinical and Biological Sciences, AOU San Luigi Gonzaga, 10043 Orbassano, Torino, Italy.
Antonella
A
Roetto
San Raffaele Scientific Institute, Division of Neuroscience, 20132 Milano, Italy.|University Vita-Salute San Raffaele, 20132 Milano, Italy.
Sonia
S
Levi
D001483:Base Sequence; D003198:Computer Simulation; D044127:Epigenesis, Genetic; D005293:Ferritins / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005621:Friedreich Ataxia / Q000235:genetics / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D008156:Luciferases / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000378:metabolism*
D024101:Mitochondrial Proteins; D014157:Transcription Factors; C556634:mitochondrial ferritin, human; D005293:Ferritins; D008156:Luciferases