Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment

Constantinides, Philip G.; Jones, Peter A.; Gevers, Wieland

doi:10.1038/267364a0

Cited by 308 publications

(161 citation statements)

References 7 publications

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“…5-aza-dC only incorporates into DNA during replication and insertion into DNA, specifically at CG sites, causes the inhibition of the mammalian DNA cytosine-C5 methyltransferase (MTase). Consequently, these compounds inhibit MTase only in the S phase of cells when they are actively dividing 38 which makes them a potent anti cancer drug.…”

Section: Mechanism Of Inhibition Of the Drugs Targeting Dna Methylationmentioning

confidence: 99%

“…37 These examples demonstrate that demethylating drugs could be applied in combined therapy with conventional anti cancer drugs. Both 5-aza-C and 5-aza-dC are chemically unstable 38 making oral application impossible and, therefore, have to be administered via subcutaneous injections. Several analogues like pseudoisocytidine 39 and 5,6 dihydro-5-aza-cytidine 40 with more stable ring systems have been developed which inhibit DNA methylation but they were not successful in clinical trials.…”

Section: Compounds Targeting Dna Mtasesmentioning

confidence: 99%

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Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

Gowher¹,

Jeltsch²

2004

Cancer Biology & Therapy

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Section: Mechanism Of Inhibition Of the Drugs Targeting Dna Methylationmentioning

confidence: 99%

Section: Compounds Targeting Dna Mtasesmentioning

confidence: 99%

Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

Gowher¹,

Jeltsch²

2004

Cancer Biology & Therapy

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“…It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226-232; Riggs AD (1975) Cytogenet Cell Genet 14(1): [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25]. This revolutionary proposal was justified by "... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development" that prevailed at the time.…”

mentioning

confidence: 99%

Notes on the role of dynamic DNA methylation in mammalian development

Bestor

Edwards

Boulard

2014

Proc. Natl. Acad. Sci. U.S.A.

207

166

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It has been nearly 40 y since it was suggested that genomic methylation patterns could be transmitted via maintenance methylation during S phase and might play a role in the dynamic regulation of gene expression during development [Holliday R, Pugh JE (1975) Science 187(4173):226-232; Riggs AD (1975) Cytogenet Cell Genet 14(1):9-25]. This revolutionary proposal was justified by "... our almost complete ignorance of the mechanism for the unfolding of the genetic program during development" that prevailed at the time. Many correlations between transcriptional activation and demethylation have since been reported, but causation has not been demonstrated and to date there is no reasonable proof of the existence of a complex biochemical system that activates and represses genes via reversible DNA methylation. Such a system would supplement or replace the conserved web of transcription factors that regulate cellular differentiation in organisms that have unmethylated genomes (such as Caenorhaditis elegans and the Dipteran insects) and those that methylate their genomes. DNA methylation does have essential roles in irreversible promoter silencing, as in the monoallelic expression of imprinted genes, in the silencing of transposons, and in X chromosome inactivation in female mammals. Rather than reinforcing or replacing regulatory pathways that are conserved between organisms that have either methylated or unmethylated genomes, DNA methylation endows genomes with the ability to subject specific sequences to irreversible transcriptional silencing even in the presence of all of the factors required for their expression, an ability that is generally unavailable to organisms that have unmethylated genomes. Structure of Genomic Methylation PatternsThe addition of a fifth base (5-methylcytosine or m 5 C) increases the maximum potential information content of DNA from 2 bits per base pair to 2.32 bits; the addition of naturally occurring oxidized forms of m 5 C (5-hydroxymethycytosine, 5-formylcytosine, and 5-carboxylcytosine) increases the information content still further, although m 5 C is much more abundant than the oxidized derivatives. The assembled and annotated fraction of the human genome contains ∼29 million CpG dinucleotides, each of which can exist in the methylated or unmethylated state.

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“…The hybrid is deficient in hypoxanthine/guanine phosphoribosyltransferase (HPRT; IMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) and, previous studies have shown that treatment of these cells with the base analog 5-azacytidine (5-Aza-Cyd) resulted in the production of HPRT' cells by reactivation of the gene on the inactive human X chromosome (10). 5-Aza-Cyd and other cytidine analogs modified in the 5-position, have marked effects on the differentiated state ofcells (11)(12)(13)(14), and we have suggested that these effects are due to the abilities of the analogs to inhibit DNA methylation (15). Because inactive X chromosomes normally replicate late in S phase (16), we have determined the cell cycle specificity of reactivation of the suppressed gene by the deoxy analog of 5-Aza-Cyd, 5-aza-2'-deoxycytidine (5-AzadCyd).…”

mentioning

confidence: 99%

Cell cycle-specific reactivation of an inactive X-chromosome locus by 5-azadeoxycytidine.

Jones¹,

Taylor²,

Mohandas³

et al. 1982

Proc. Natl. Acad. Sci. U.S.A.

132

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Three cytidine analogs containing modifications in the 5-position of the cytosine ring (5-azacytidine, 5-aza-2'-deoxycytidine and pseudoisocytidine) induced the expression of human hypoxanthine/guanine phosphoribosyltransferase (IMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) gene (HPRT) from a structurally normal inactive human X chromosome retained in a mouse-human somatic cell hybrid. Between 0.1% and 8% of the cells surviving treatment with these analogs were able to form colonies in selective medium (hypoxanthine/aminopterin/thymidine/glycine medium), but two other analogs, 5-fluoro-2'-deoxycytidine and 5,6-dihydro-5-azacytidine, did not induce HPRT expression. The inactive X chromosome present in the hybrid, was found to be late replicating, and experiments with synchronized cells showed that the induction of HPRT expression by 5-aza-2'-deoxycytidine occurred maximally in.cells treated in the latter half of the S phase. Two division cycles were required after analog treatment for the highest frequency of expression of the induced gene. Because these analogs are powerful inhibitors of the methylation of cytosine residues in DNA, the results imply that demethylation of specific DNA sequences may be required for the reexpression of human HPRT.The successful passage through the S phase in the eukaryotic cell cycle requires not only the accurate replication ofthe genotype but also the faithful copying of the cellular phenotype.

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Functional striated muscle cells from non-myoblast precursors following 5-azacytidine treatment

Cited by 308 publications

References 7 publications

Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

Mechanism of inhibition of DNA methyltransferases by cytidine analogs in cancer therapy

Notes on the role of dynamic DNA methylation in mammalian development

Cell cycle-specific reactivation of an inactive X-chromosome locus by 5-azadeoxycytidine.

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