Transcriptional control of house keeping genes by Sp1 and histone acetylation: molecular mechanisms and therapeutic potential
Lead Research Organisation:
Imperial College London
Department Name: Dept of Medicine
Abstract
We have recently described a disease caused by a defect in a gene required for the formation of a molecule called GPI. Affected children suffer from life-threatening blood clots and severe epilepsy.
We found that in the DNA of these patients, attachment of a molecule called acetyl group, required for the proper function of genes, was very low; and that a drug called butyrate could restore attachment of the acetyl groups and thus restore the function of the gene. Furthermore, treatment of a patient with butyrate led to complete cessation of lifelong and uncontrollable seizures.
With this work we would like to understand better the role of these acetyl groups in causing disease and how butyrate exerts its beneficial effect. We will also explore whether butyrate can benefit patients with other inherited and often lethal disorders for which no specific treatment exists.
We found that in the DNA of these patients, attachment of a molecule called acetyl group, required for the proper function of genes, was very low; and that a drug called butyrate could restore attachment of the acetyl groups and thus restore the function of the gene. Furthermore, treatment of a patient with butyrate led to complete cessation of lifelong and uncontrollable seizures.
With this work we would like to understand better the role of these acetyl groups in causing disease and how butyrate exerts its beneficial effect. We will also explore whether butyrate can benefit patients with other inherited and often lethal disorders for which no specific treatment exists.
Technical Summary
Sp1 is a general transcription factor (TF) that can modulate histone acetylation and thus transcription by recruiting to the promoter histone acetyltransferases (HAT) and deacetylases (HDAC). For some genes, enhanced transcription in response to HDAC inhibition requires Sp1 binding to the promoter. We have shown that a single nucleotide substitution at the promoter of PIGM, encoding a mannosyltransferase required for glycosylphosphatidylinositol (GPI) synthesis, results in Sp1 binding disruption, histone hypoacetylation, reduced transcription and eventually inherited GPI deficiency (IGD). HDAC inhibitor butyrate restored acetylation in a Sp1-dependent manner, PIGM transcription, GPI biosynthesis and was of great therapeutic value in a patient with IGD.
The aim of this project is to dissect the transcriptional regulation of house-keeping genes, as exemplified by PIGM, by Sp1-dependent histone acetylation and explore whether its butyrate-mediated modulation could be of therapeutic potential in inherited disorders of glycolysis.
For this purpose, using human PIGM and glycolytic enzyme deficient cell lines and a murine knock-in model of inherited GPI deficiency the relative roles of Sp1, HAT/HDAC and other TF such as GATA-1 in regulating transcription of PIGM and genes of the glycolytic pathway at baseline and in response to HDAC inhibitors will be studied.
The aim of this project is to dissect the transcriptional regulation of house-keeping genes, as exemplified by PIGM, by Sp1-dependent histone acetylation and explore whether its butyrate-mediated modulation could be of therapeutic potential in inherited disorders of glycolysis.
For this purpose, using human PIGM and glycolytic enzyme deficient cell lines and a murine knock-in model of inherited GPI deficiency the relative roles of Sp1, HAT/HDAC and other TF such as GATA-1 in regulating transcription of PIGM and genes of the glycolytic pathway at baseline and in response to HDAC inhibitors will be studied.