Transcriptional and epigenetic basis for restoration of G6PD enzymatic activity in human G6PD-deficient cells

被引：21

作者：

Makarona, Kalliopi ^{[1
]}

Caputo, Valentina S. ^{[1
]}

Costa, Joana R. ^{[1
]}

Liu, Binbin ^{[2
,3
,4
]}

O'Connor, David ^{[1
]}

Iskander, Deena ^{[1
]}

Roper, David ^{[5
]}

Robertson, Lynn ^{[5
]}

Bhatnagar, Neha ^{[1
]}

Terpos, Evangelos ^{[6
]}

Georgiou, Elisabeth ^{[7
]}

Papaioannou, Maria ^{[8
]}

Layton, D. Mark ^{[1
]}

Luzzatto, Lucio ^{[9
]}

Roberts, Irene ^{[2
,3
,4
]}

Karadimitris, Anastasios ^{[1
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Med, Ctr Haematol, London W12 0NN, England

[2] Univ Oxford, Childrens Hosp, Dept Paediat, Oxford, England

[3] Univ Oxford, Weatherall Inst Mol Med, Mol Haematol Unit, Oxford, England

[4] John Radcliffe Hosp, Oxford OX3 9DU, England

[5] Imperial Coll Healthcare Natl Hlth Serv Trust, Hammersmith Hosp, Blood Sci Serv, London, England

[6] Univ Athens, Sch Med, Dept Clin Therapeut, GR-11527 Athens, Greece

[7] Aristotle Univ Thessaloniki, Dept Biol Chem, Sch Med, GR-54006 Thessaloniki, Greece

[8] Aristotle Univ Thessaloniki, Sch Med, Amer Hellen Educ Progress Assoc Hosp, GR-54006 Thessaloniki, Greece

[9] Ist Toscano Tumori, Florence, Italy

来源：

BLOOD | 2014年 / 124卷 / 01期

基金：

英国医学研究理事会;

关键词：

HISTONE DEACETYLASE INHIBITORS; INHERITED GPI DEFICIENCY; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE GENE; PHENYLBUTYRATE; IDENTIFICATION; ACETYLATION; EXPRESSION; PROMOTER; MUTATION; THERAPY;

D O I：

10.1182/blood-2014-02-553792

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

HDAC inhibitors (HDACi) increase transcription of some genes through histone hyper-acetylation. To test the hypothesis that HDACi-mediated enhanced transcription might be of therapeutic value for inherited enzyme deficiency disorders, we focused on the glycolytic and pentose phosphate pathways (GPPPs). We show that among the 16 genes of the GPPPs, HDACi selectively enhance transcription of glucose 6-phosphate dehydrogenase (G6PD). This requires enhanced recruitment of the generic transcription factor Sp1, with commensurate recruitment of histone acetyltransferases and deacetylases, increased histone acetylation, and polymerase II recruitment to G6PD. These G6PD-selective transcriptional and epigenetic events result in increased G6PD transcription and ultimately restored enzymatic activity in B cells and erythroid precursor cells from patients with G6PD deficiency, a disorder associated with acute or chronic hemolytic anemia. Therefore, restoration of enzymatic activity in G6PD-deficient nucleated cells is feasible through modulation of G6PD transcription. Our findings also suggest that clinical consequences of pathogenic missense mutations in proteins with enzymatic function can be overcome in some cases by enhancement of the transcriptional output of the affected gene.

引用

页码：134 / 141

页数：8

共 38 条

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