Research output: Contribution to journal › Article › peer-review
Inhibitors of Histone Deacetylases Are Weak Activators of the FMR1 Gene in Fragile X Syndrome Cell Lines. / Dolskiy, Alexander A.; Pustylnyak, Vladimir O.; Yarushkin, Andrey A. et al.
In: BioMed Research International, Vol. 2017, 3582601, 01.01.2017, p. 3582601.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Inhibitors of Histone Deacetylases Are Weak Activators of the FMR1 Gene in Fragile X Syndrome Cell Lines
AU - Dolskiy, Alexander A.
AU - Pustylnyak, Vladimir O.
AU - Yarushkin, Andrey A.
AU - Lemskaya, Natalya A.
AU - Yudkin, Dmitry V.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Fragile X syndrome is the most common cause of inherited intellectual disability in humans. It is a result of CGG repeat expansion in the 5′ untranslated region (5′ UTR) of the FMR1 gene. This gene encodes the FMRP protein that is involved in neuronal development. Repeat expansion leads to heterochromatinization of the promoter, gene silencing, and the subsequent absence of FMRP. To date, there is no specific therapy for the syndrome. All treatments in clinic practice provide symptomatic therapy. The development of drug therapy for Fragile X syndrome treatment is connected with the search for inhibitors of enzymes that are responsible for heterochromatinization. Here, we report a weak transcriptional activity of the FMR1 gene and the absence of FMRP protein after Fragile X syndrome cell lines treatment with two FDA approved inhibitors of histone deacetylases, romidepsin and vorinostat. We demonstrate that romidepsin, an inhibitor of class I histone deacetylases, does not activate FMR1 expression in patient cell cultures, whereas vorinostat, an inhibitor of classes I and II histone deacetylases, activates a low level of FMR1 expression in some patient cell lines.
AB - Fragile X syndrome is the most common cause of inherited intellectual disability in humans. It is a result of CGG repeat expansion in the 5′ untranslated region (5′ UTR) of the FMR1 gene. This gene encodes the FMRP protein that is involved in neuronal development. Repeat expansion leads to heterochromatinization of the promoter, gene silencing, and the subsequent absence of FMRP. To date, there is no specific therapy for the syndrome. All treatments in clinic practice provide symptomatic therapy. The development of drug therapy for Fragile X syndrome treatment is connected with the search for inhibitors of enzymes that are responsible for heterochromatinization. Here, we report a weak transcriptional activity of the FMR1 gene and the absence of FMRP protein after Fragile X syndrome cell lines treatment with two FDA approved inhibitors of histone deacetylases, romidepsin and vorinostat. We demonstrate that romidepsin, an inhibitor of class I histone deacetylases, does not activate FMR1 expression in patient cell cultures, whereas vorinostat, an inhibitor of classes I and II histone deacetylases, activates a low level of FMR1 expression in some patient cell lines.
KW - Cell Line
KW - Cell Survival/drug effects
KW - Depsipeptides/pharmacology
KW - Fragile X Mental Retardation Protein/genetics
KW - Fragile X Syndrome/drug therapy
KW - Gene Expression Regulation/drug effects
KW - Heterochromatin/genetics
KW - Histone Deacetylase Inhibitors/administration & dosage
KW - Humans
KW - Hydroxamic Acids/pharmacology
KW - Male
KW - Promoter Regions, Genetic/genetics
KW - Trinucleotide Repeat Expansion/genetics
KW - Vorinostat
KW - ALLELES
KW - MECHANISM
KW - TRANSCRIPTION
KW - REACTIVATION
KW - HETEROCHROMATIN
KW - EXPRESSION
KW - PCR
UR - http://www.scopus.com/inward/record.url?scp=85042158714&partnerID=8YFLogxK
U2 - 10.1155/2017/3582601
DO - 10.1155/2017/3582601
M3 - Article
C2 - 29209628
AN - SCOPUS:85042158714
VL - 2017
SP - 3582601
JO - BioMed Research International
JF - BioMed Research International
SN - 2314-6133
M1 - 3582601
ER -
ID: 9960991