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 -