| 1. |
- Kanduri, Meena, 1974, et al.
(författare)
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A key role for EZH2 in epigenetic silencing of HOX genes in mantle cell lymphoma
- 2013
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 8:12, s. 1280-8
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Tidskriftsartikel (refereegranskat)abstract
- The chromatin modifier EZH2 is overexpressed and associated with inferior outcome in mantle cell lymphoma (MCL). Recently, we demonstrated preferential DNA methylation of HOX genes in MCL compared with chronic lymphocytic leukemia (CLL), despite these genes not being expressed in either entity. Since EZH2 has been shown to regulate HOX gene expression, to gain further insight into its possible role in differential silencing of HOX genes in MCL vs. CLL, we performed detailed epigenetic characterization using representative cell lines and primary samples. We observed significant overexpression of EZH2 in MCL vs. CLL. Chromatin immune precipitation (ChIP) assays revealed that EZH2 catalyzed repressive H3 lysine 27 trimethylation (H3K27me3), which was sufficient to silence HOX genes in CLL, whereas in MCL H3K27me3 is accompanied by DNA methylation for a more stable repression. More importantly, hypermethylation of the HOX genes in MCL resulted from EZH2 overexpression and subsequent recruitment of the DNA methylation machinery onto HOX gene promoters. The importance of EZH2 upregulation in this process was further underscored by siRNA transfection and EZH2 inhibitor experiments. Altogether, these observations implicate EZH2 in the long-term silencing of HOX genes in MCL, and allude to its potential as a therapeutic target with clinical impact.
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| 2. |
- Pandey, Gaurav Kumar, et al.
(författare)
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The risk-associated long noncoding RNA NBAT-1 controls neuroblastoma progression by regulating cell proliferation and neuronal differentiation.
- 2014
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Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 26:5, s. 722-737
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is an embryonal tumor of the sympathetic nervous system and the most common extracranial tumor of childhood. By sequencing transcriptomes of low- and high-risk neuroblastomas, we detected differentially expressed annotated and nonannotated long noncoding RNAs (lncRNAs). We identified a lncRNA neuroblastoma associated transcript-1 (NBAT-1) as a biomarker significantly predicting clinical outcome of neuroblastoma. CpG methylation and a high-risk neuroblastoma associated SNP on chromosome 6p22 functionally contribute to NBAT-1 differential expression. Loss of NBAT-1 increases cellular proliferation and invasion. It controls these processes via epigenetic silencing of target genes. NBAT-1 loss affects neuronal differentiation through activation of the neuronal-specific transcription factor NRSF/REST. Thus, loss of NBAT-1 contributes to aggressive neuroblastoma by increasing proliferation and impairing differentiation of neuronal precursors.
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| 3. |
- Kanduri, Chandrasekhar, 1967
(författare)
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Kcnq1ot1: A chromatin regulatory RNA
- 2011
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Ingår i: SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY. - 1084-9521. ; 22:4, s. 343-350
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Forskningsöversikt (refereegranskat)
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| 4. |
- Matthieu, Meryet-Figuiere, et al.
(författare)
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Temporal separation of replication and transcription during S-phase progression.
- 2014
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Ingår i: Cell Cycle. - : Informa UK Limited. - 1538-4101 .- 1551-4005. ; 13:20, s. 3241-3248
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Tidskriftsartikel (refereegranskat)abstract
- Transcriptional events during S-phase are critical for cell cycle progression. Here, by using a nascent RNA capture assay coupled with high-throughput sequencing, we determined the temporal patterns of transcriptional events that occur during S-phase. We show that genes involved in critical S-phase-specific biological processes such as nucleosome assembly and DNA repair have temporal transcription patterns across S-phase that are not evident from total RNA levels. By comparing transcription timing with replication timing in S-phase, we show that early replicating genes show increased transcription late in S-phase whereas late replicating genes are predominantly transcribed early in S-phase. Global anti-correlation between replication and transcription timing was observed only based on nascent RNA but not total RNA. Our data provides a detailed view of ongoing transcriptional events during the S-phase of cell cycle, and supports that transcription and replication are temporally separated.
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| 5. |
- Mohammad, F., et al.
(författare)
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Long noncoding RNA-mediated maintenance of DNA methylation and transcriptional gene silencing
- 2012
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 139:15, s. 2792-2803
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Tidskriftsartikel (refereegranskat)abstract
- Establishment of silencing by noncoding RNAs (ncRNAs) via targeting of chromatin remodelers is relatively well investigated; however, their role in the maintenance of silencing is poorly understood. Here, we explored the functional role of the long ncRNA Kcnq1ot1 in the maintenance of transcriptional gene silencing in the one mega-base Kcnq1 imprinted domain in a transgenic mouse model. By conditionally deleting the Kcnq1ot1 ncRNA at different stages of mouse development, we suggest that Kcnq1ot1 ncRNA is required for the maintenance of the silencing of ubiquitously imprinted genes (UIGs) at all developmental stages. In addition, Kcnq1ot1 ncRNA is also involved in guiding and maintaining the CpG methylation at somatic differentially methylated regions flanking the UIGs, which is a hitherto unknown role for a long ncRNA. On the other hand, silencing of some of the placental-specific imprinted genes (PIGs) is maintained independently of Kcnq1ot1 ncRNA. Interestingly, the non-imprinted genes (NIGs) that escape RNA-mediated silencing are enriched with enhancer-specific modifications. Taken together, this study illustrates the gene-specific maintenance mechanisms operational at the Kcnq1 locus for tissue-specific transcriptional gene silencing and activation.
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| 6. |
- Mondal, Tanmoy, 1981, et al.
(författare)
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Maintenance of epigenetic information: a noncoding RNA perspective
- 2013
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Ingår i: Chromosome Research. - : Springer Science and Business Media LLC. - 0967-3849 .- 1573-6849. ; 21:6-7, s. 615-625
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Tidskriftsartikel (refereegranskat)abstract
- Along the lines of established players like chromatin modifiers and transcription factors, noncoding RNA (ncRNA) are now widely accepted as one of the key regulatory molecules in epigenetic regulation of transcription. With increasing evidence of ncRNAs in the establishment of gene silencing through their ability to interact with major chromatin modifiers, in the current review, we discuss their prospective role in the area of inheritance and maintenance of these established silenced states which can be reversible or irreversible in nature. In addition, we attempt to understand and speculate how these RNA dependent or independent maintenance mechanisms differ between each other in a developmental stage, tissue, and gene-specific manner in different biological contexts by utilizing known/unknown regulatory factors.
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| 7. |
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| 8. |
- Reinius, Björn, et al.
(författare)
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Abundance of female-biased and paucity of male-biased somatically expressed genes on the mouse X-chromosome.
- 2012
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Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: Background: Empirical evaluations of sexually dimorphic expression of genes on the mammalian X-chromosome are needed to understand the evolutionary forces and the gene-regulatory mechanisms controlling this chromosome. We performed a large-scale sex-bias expression analysis of genes on the X-chromosome in six different somatic tissues from mouse. Results: Our results show that the mouse X-chromosome is enriched with female-biased genes and depleted of male-biased genes. This suggests that feminisation as well as de-masculinisation of the X-chromosome has occurred in terms of gene expression in non-reproductive tissues. Several mechanisms may be responsible for the control of female-biased expression on chromosome X, and escape from X-inactivation is a main candidate. We confirmed escape in case of Tmem29 using RNA-FISH analysis. In addition, we identified novel female-biased non-coding transcripts located in the same female-biased cluster as the well-known coding X-inactivation escapee Kdm5c, likely transcribed from the transition-region between active and silenced domains. We also found that previously known escapees only partially explained the overrepresentation of female-biased X-genes, particularly for tissue-specific female-biased genes. Therefore, the gene set we have identified contains tissue-specific escapees and/or genes controlled by other sexually skewed regulatory mechanisms. Analysis of gene age showed that evolutionarily old X-genes (>100 myr, preceding the radiation of placental mammals) are more frequently female-biased than younger genes. Conclusion: Altogether, our results have implications for understanding both gene regulation and gene evolution of mammalian X-chromosomes, and suggest that the final result in terms of the X-gene composition (masculinisation versus feminisation) is a compromise between different evolutionary forces acting on reproductive and somatic tissues.
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| 9. |
- Reinius, Björn, et al.
(författare)
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Elevated Expression of H19 and Igf2 in the Female Mouse Eye
- 2013
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- The catalogue of genes expressed at different levels in the two sexes is growing, and the mechanisms underlying sex differences in regulation of the mammalian transcriptomes are being explored. Here we report that the expression of the imprinted non-protein-coding maternally expressed gene H19 was female-biased specifically in the female mouse eye (1.9-fold, p = 3.0E−6) while not being sex-biased in other somatic tissues. The female-to-male expression fold-change of H19 fell in the range expected from an effect of biallelic versus monoallelic expression. Recently, the possibility of sex-specific parent-of-origin allelic expression has been debated. This led us to hypothesize that H19 might express biallelically in the female mouse eye, thus escape its silencing imprint on the paternal allele specifically in this tissue. We therefore performed a sex-specific imprinting assay of H19 in female and male eye derived from a cross between Mus musculus and Mus spretus. However, this analysis demonstrated that H19 was exclusively expressed from the maternal gene copy, disproving the escape hypothesis. Instead, this supports that the female-biased expression of H19 is the result of upregulation of the single maternal. Furthermore, if H19 would have been expressed from both gene copies in the female eye, an associated downregulation of Insulin-like growth factor 2 (Igf2) was expected, since H19 and Igf2 compete for a common enhancer element located in the H19/Igf2 imprinted domain. On the contrary we found that also Igf2 was significantly upregulated in its expression in the female eye (1.2-fold, p = 6.1E−3), in further agreement with the conclusion that H19 is monoallelically elevated in females. The female-biased expression of H19 and Igf2 specifically in the eye may contribute to our understanding of sex differences in normal as well as abnormal eye physiology and processes.
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