Bidirectional Silencing and DNA Methylation-sensitive Methylation-spreading Properties of the Kcnq1 Imprinting Control Region Map to the Same Regions

Thakur, Noopur; Kanduri, Meena; Holmgren, Claes; Mukhopadhyay, Rituparna; Kanduri, Chandrasekhar

doi:10.1074/jbc.m212203200

Cited by 39 publications

(46 citation statements)

References 16 publications

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“…It has been reported that DMR-LIT1 are an orientation-independent silencer (Du et al, 2003;ManciniDiNardo et al, 2003;Thakur et al, 2003). Thakur et al (2003) proposed that a repressive chromatin structure established at DMR-LIT1 might propagate bidirectionally along the DNA to inactivate neighboring genes.…”

Section: Discussionmentioning

confidence: 99%

“…Thakur et al (2003) proposed that a repressive chromatin structure established at DMR-LIT1 might propagate bidirectionally along the DNA to inactivate neighboring genes. Since LIT1 is an antisense noncoding transcript, the establishment and propagation of a repressive chromatin structure might be similar to that of Igf2r ICR, which contains Air, an antisense noncoding transcript of Igf2r (Sleutels et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Soejima¹,

Nakagawachi²,

Zhao³

et al. 2004

Oncogene

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The putative tumor suppressor CDKN1C is an imprinted gene at 11p15.5, a well-known imprinted region often deleted in tumors. The absence of somatic mutations and the frequent diminished expression in tumors would suggest that CDKN1C expression is regulated epigenetically. It has been, however, controversial whether the diminution is caused by imprinting disruption of the CDKN1C/LIT1 domain or by promoter hypermethylation of CDKN1C itself. To clarify this, we investigated the CpG methylation index of the CDKN1C promoter and the differentially methylated region of the LIT1 CpG island (differentially methylated region (DMR)-LIT1), an imprinting control region of the domain, and CDKN1C expression in esophageal cancer cell lines. CDKN1C expression was diminished in 10 of 17 lines and statistically correlated with the loss of methylation at DMR-LIT1 in all but three. However, there was no statistical correlation between CDKN1C promoter MI and CDKN1C expression. Furthermore, loss of CpG methylation was associated with loss of histone H3 lysine 9 (H3K9) methylation at DMR-LIT1. Histone modifications at CDKN1C promoter were not correlated with CDKN1C expression. The data suggested that the diminished CDKN1C expression is associated with the loss of methylation of CpG and H3K9 at DMR-LIT1, not by its own promoter CpG methylation, and is involved in esophageal cancer, implying that DMR-LIT1 epigenetically regulates CDKN1C expression not through histone modifications at CDKN1C promoter, but through that of DMR-LIT1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Soejima¹,

Nakagawachi²,

Zhao³

et al. 2004

Oncogene

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“…ment of the genes on both sides of the KvDMR and their varied expression patterns make an enhancer-blocking model difficult to orchestrate. Indeed using in vitro transfection assays, the KvDMR behaved as a silencer rather than as an enhancer blocker (Mancini-DiNardo et al 2003;Thakur et al 2003). The other well-established mechanism for silencing imprinted genes is the RNAdependent silencing by an antisense transcript, as occurs at the Igf2r locus in the mouse (Sleutels et al 2002).…”

mentioning

confidence: 99%

Elongation of theKcnq1ot1transcript is required for genomic imprinting of neighboring genes

Mancini‐DiNardo

Steele²,

Levorse³

et al. 2006

Genes Dev.

406

380

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The imprinted gene cluster at the telomeric end of mouse chromosome 7 contains a differentially methylated CpG island, KvDMR, that is required for the imprinting of multiple genes, including the genes encoding the maternally expressed placental-specific transcription factor ASCL2, the cyclin-dependent kinase CDKN1C, and the potassium channel KCNQ1. The KvDMR, which maps within intron 10 of Kcnq1, contains the promoter for a paternally expressed, noncoding, antisense transcript, Kcnq1ot1. A 244-base-pair deletion of the promoter on the paternal allele leads to the derepression of all silent genes tested. To distinguish between the loss of silencing as the consequence of the absence of transcription or the transcript itself, we prematurely truncated the Kcnq1ot1 transcript by inserting a transcriptional stop signal downstream of the promoter. We show that the lack of a full-length Kcnq1ot1 transcript on the paternal chromosome leads to the expression of genes that are normally paternally repressed. Finally, we demonstrate that five highly conserved repeats residing at the 5 end of the Kcnq1ot1 transcript are not required for imprinting at this locus.

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“…Taken together, these observations demonstrate that NF-Y transcription factor is involved in the maintenance of differential epigenetic marks at the Kcnq1 ICR. We have earlier documented that the Kcnq1 ICR spreads de novo methylation into the flanking H19 coding region (8) and that this property occurs as a consequence of antisense RNA-mediated silencing. Because antisense transcription is lost in the PS4CAT1-3 constructs, we tested for the methylation spreading property of the Kcnq1 ICR in the PS4CAT1-3 construct.…”

Section: Nf-y Transcription Factor Maintains Differential Epigeneticmentioning

confidence: 99%

“…We have earlier documented that the Kcnq1 ICR behaves as a bidirectional silencer (8). More recently, by selectively deleting the region spanning the antisense promoter and attenuating the antisense transcription by poly(A) sequence, we have shown that the production of an antisense RNA, Kcnq1ot1, is critical in the bidirectional silencing property of the Kcnq1 ICR (3).…”

mentioning

confidence: 95%

NF-Y Regulates the Antisense Promoter, Bidirectional Silencing, and Differential Epigenetic Marks of the Kcnq1 Imprinting Control Region

Pandey

Ceribelli²,

Singh

et al. 2004

Journal of Biological Chemistry

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Antisense transcription has been shown to be one of the hierarchies that control gene expression in eukaryotes. Recently, we have documented that the mouse Kcnq1 imprinting control region (ICR) harbors bidirectional silencing property, and this feature is linked to an antisense RNA, Kcnq1ot1. In this investigation, using genomic footprinting, we have identified three NF-Y transcription factor binding sites appearing in a methylation-sensitive manner in the Kcnq1ot1 promoter. By employing a dominant negative mutant to the NF-Y transcription factor, we have shown that the NF-Y transcription factor positively regulates antisense transcription. Selective mutation of the conserved nucleotides in the NF-Y binding sites resulted in the loss of antisense transcription. The loss of antisense transcription from the Kcnq1ot1 promoter coincides with an enrichment in the levels of deacetylation and methylation at the lysine 9 residue of histone H3 and DNA methylation at the CpG residues, implying a crucial role for the NF-Y transcription factor in organizing the parent of origin-specific chromatin conformation in the Kcnq1 ICR. Parallel to the loss of antisense transcription, the loss of silencing of the flanking reporter genes was observed, suggesting that NF-Y-mediated Kcnq1ot1 transcription is critical in the bidirectional silencing process of the Kcnq1 ICR. These data highlight the NF-Y transcription factor as a crucial regulator of antisense promoter-mediated bidirectional silencing and the parent of origin-specific epigenetic marks at the Kcnq1 ICR. More importantly, for the first time, we document that NF-Y is involved in maintaining the antisense promoter activity against strong silencing conditions.

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Bidirectional Silencing and DNA Methylation-sensitive Methylation-spreading Properties of the Kcnq1 Imprinting Control Region Map to the Same Regions

Cited by 39 publications

References 16 publications

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Silencing of imprinted CDKN1C gene expression is associated with loss of CpG and histone H3 lysine 9 methylation at DMR-LIT1 in esophageal cancer

Elongation of theKcnq1ot1transcript is required for genomic imprinting of neighboring genes

NF-Y Regulates the Antisense Promoter, Bidirectional Silencing, and Differential Epigenetic Marks of the Kcnq1 Imprinting Control Region

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