Hydroxamide derivatives of short-chain fatty acids are potent inducers of human fetal globin gene expression

Skarpidi, Evangelia; Cao, Hua; Heltweg, Birgit; White, Brian; Marhenke, Ronald L; Jung, Manfred; Stamatoyannopoulos, George

doi:10.1016/s0301-472x(02)01030-5

Cited by 25 publications

(22 citation statements)

References 43 publications

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“…7 Two other hydroxamic acid derivatives, SAHA and SBHA, induce ␥ globin gene expression in concentrations that are approximately 2 orders of magnitude lower than those of butyrate and propionate. 7 Here, we report induction of ␥ gene expression by 3 classes of HDAC inhibitors: analogues of trichostatin A, analogues of trapoxin, and scriptaid and its analogues. The most potent inducers in human BFUe cultures were the trichostatin analog M344, the trapoxin analogues SW68 and SW70, and scriptaid.…”

Section: Discussionmentioning

confidence: 99%

“…We have also found a correlation between concentrations of hydroxamic acid derivatives which inhibit in HDAC and those which induce ␥ globin gene activity. 7 In the present study we investigated 3 series of HDAC inhibitors for their effects on fetal globin gene expression. We found that low micromolar concentrations of several HDAC inhibitors induce ␥ gene promoter activity, increase the levels of ␥ mRNA, and increase the frequency of fetal hemoglobin-containing erythroblasts.…”

Section: Introductionmentioning

confidence: 99%

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Induction of human γ globin gene expression by histone deacetylase inhibitors

Cao

Stamatoyannopoulos

Jung

2004

Blood

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We investigated the induction of human ␥ globin gene activity by 3 classes of histone deacetylase inhibitors: amide analogues of trichostatin A, hydroxamic acid analogues of trapoxin, and scriptaid and its analogues. The screening consisted of measuring the effects of these compounds on ␥ and ␤ human gene promoter activity by using cultures of GM979 cells stably transfected with a construct containing a ␥ promoter linked to firefly luciferase and a ␤ promoter linked to renilla

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Induction of human γ globin gene expression by histone deacetylase inhibitors

Cao

Stamatoyannopoulos

Jung

2004

Blood

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“…It is known from comparative studies of hydroxamic acids and "parent" carboxylic acids (e.g., butyryl-hydroxamate and butyrate) that carboxylic acid derivatives reveal a Ͼ30-fold increase in IC 50 values compared to those of the corresponding hydroxamates (26). Thus, using the two-step assay to reveal whether Zn 2ϩ ions are also part of the active site of FB188 HDAH, we studied the inhibition of the enzyme by HDAC inhibitor SAHA and its carboxylic acid analogue SA-OH (Fig.…”

Section: Figmentioning

confidence: 99%

A New Amidohydrolase from Bordetella or Alcaligenes Strain FB188 with Similarities to Histone Deacetylases

et al. 2004

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The full-length gene encoding the histone deacetylase (HDAC)-like amidohydrolase (HDAH) from Bordetella or Alcaligenes (Bordetella/Alcaligenes) strain FB188 (DSM 11172) was cloned using degenerate primer PCR combined with inverse-PCR techniques and ultimately expressed in Escherichia coli. The expressed enzyme was biochemically characterized and found to be similar to the native enzyme for all properties examined. Nucleotide sequence analysis revealed an open reading frame of 1,110 bp which encodes a polypeptide with a theoretical molecular mass of 39 kDa. Interestingly, peptide sequencing disclosed that the N-terminal methionine is lacking in the mature wild-type enzyme, presumably due to the action of methionyl aminopeptidase. Sequence database searches suggest that the new amidohydrolase belongs to the HDAC superfamily, with the closest homologs being found in the subfamily assigned acetylpolyamine amidohydrolases (APAH). The APAH subfamily comprises enzymes or putative enzymes from such diverse microorganisms as Pseudomonas aeruginosa, Archaeoglobus fulgidus, and the actinomycete Mycoplana ramosa (formerly M. bullata). The FB188 HDAH, however, is only moderately active in catalyzing the deacetylation of acetylpolyamines. In fact, FB188 HDAH exhibits significant activity in standard HDAC assays and is inhibited by known HDAC inhibitors such as trichostatin A and suberoylanilide hydroxamic acid (SAHA). Several lines of evidence indicate that the FB188 HDAH is very similar to class 1 and 2 HDACs and contains a Zn 2؉ ion in the active site which contributes significantly to catalytic activity. Initial biotechnological applications demonstrated the extensive substrate spectrum and broad optimum pH range to be excellent criteria for using the new HDAH from Bordetella/ Alcaligenes strain FB188 as a biocatalyst in technical biotransformations, e.g., within the scope of human immunodeficiency virus reverse transcriptase inhibitor synthesis.Class 1 and 2 histone deacetylases (HDACs) (19), acetoin utilization proteins, and acetylpolyamine amidohydrolases (APAH) are members of the same superfamily (17) and may very well descend from a common ancestor (14). Sequence comparison reveals that all three classes of proteins share a number of common motifs. Additionally, they show significant functional similarities such as recognition of acetylated aminoalkyl groups and the removal of the acetyl moiety by cleaving an amide bond. Interestingly, the biological role of APAH is still a matter of speculation, although these enzymes are thought to be involved in degradative pathways of polyamines (20), particularly in the deacetylation of acetylpolyamines (23). However, experimental evidence to support this idea is still rather scarce. To date, only the APAH from Mycoplana ramosa has been described in detail. While some APAH were reported to cleave only acetylputrescine in vitro, M. ramosa APAH was described as less specific in the same experiments (23). Besides having a role in the degradative pathways of polyamines, APAH could, i...

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“…As previously shown, some HDAC inhibitors are able to induce ␥ globin gene reactivation in human erythroid cells. [57][58][59][60][61] From these studies, it is unclear whether or not these HDAC inhibitors directly influence histone acetylation of the human ␤-globin locus. On the other hand, treatment of bone marrow cells with HDAC inhibitors is not sufficient to modify the pattern of globin gene expression in adult ␤-yeast artificial chromosome (␤-YAC) transgenic mice 62 carrying the whole human ␤-globin locus.…”

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confidence: 99%

Developmental stage–specific epigenetic control of human β-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcriptional activation

Bottardi

Aumont

Grosveld

et al. 2003

Blood

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To study epigenetic regulation of the human ␤-globin locus during hematopoiesis, we investigated patterns of histone modification and chromatin accessibility along this locus in hematopoietic progenitor cells (HPCs) derived from both humans and transgenic mice. We demonstrate that the developmentally related activation of human ␤-like globin genes in humans and transgenic mice HPCs is preceded by a wave of gene-specific histone H3 hyperacetylation and K4 dimethylation. In erythroid cells, expression of ␤-like globin genes is associated with histone hyperacetylation along these genes and, surprisingly, with local deacetylation at active promoters. We also show that endogenous mouse ␤ major and human ␤-like genes are subject to different epigenetic control mechanisms in HPCs. This difference is likely due to intrinsic properties of the human ␤-globin locus since, in transgenic mice, this locus is epigenetically regulated in the same manner as in human HPCs. Our results suggest that a defined pattern of histone H3 acetylation/dimethylation is important for specific activation of human globin promoters during development in human and transgenic HPCs. We propose that this transient acetylation/dimethylation is involved in gene-specific potentiation in HPCs (ie, before extensive chromatin remodeling and transcription take place in erythroid cells). IntroductionRegulation of the "on/off" state of transcription in eukaryotes plays a critical role in embryogenesis and cellular differentiation. 1 This heritable process is linked to epigenetic states involving DNA methylation and changes in chromatin structure, which maintain transcriptional status throughout mitosis and DNA replication. Eukaryotic gene activation results from the interplay of trans-activators and/or repressors with nucleosome-modifying and/or -remodeling factors. Indeed, nucleosome organization is a key component of epigenetic regulation (Felsenfeld and Groudine 2 and references therein). Observations made in recent years have led to the notion that a combination of histone modifications such as acetylation, phosphorylation, and methylation generates a histone code that regulates the use of information from the genetic code. 3 These posttranslational modifications of histones are important determinants in nucleosome-nucleosome and nucleosome-DNA interactions 4 and provide precise patterns recognized and bound by specific proteins.Epigenetic regulation of transcription appears to play an important role during hematopoiesis. For example, abnormal patterns of DNA methylation and chromatin structure are common traits in hematologic malignancies, 5 and chromosomal translocations that change the activity of histone acetyltransferases and histone deacetylases (HDACs) are associated with several forms of leukemia. 6 Hematopoiesis is characterized by a gradual commitment of multipotent hematopoietic progenitors to become bipotent or unipotent progenitors and, eventually, mature blood cells. In hematopoietic progenitor cells (HPCs), lineage-specific genes are thou...

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Hydroxamide derivatives of short-chain fatty acids are potent inducers of human fetal globin gene expression

Cited by 25 publications

References 43 publications

Induction of human γ globin gene expression by histone deacetylase inhibitors

Induction of human γ globin gene expression by histone deacetylase inhibitors

A New Amidohydrolase from Bordetella or Alcaligenes Strain FB188 with Similarities to Histone Deacetylases

Developmental stage–specific epigenetic control of human β-globin gene expression is potentiated in hematopoietic progenitor cells prior to their transcriptional activation

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