Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain

Lee, Jeannie T.; Lu, Naifung; Han, Yoon Chi

doi:10.1073/pnas.96.7.3836

Cited by 110 publications

(73 citation statements)

References 41 publications

(54 reference statements)

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“…The GENCODE v7 catalog of human lncRNAs estimates a total number of 14,880 lncRNAs (27), but with the rapid increase in RNA sequencing (RNA-seq) data, the number of lncRNAs may soon overcome that of coding genes. lncRNAs have been associated with diverse functions, including X-chromosome inactivation (28,29), differentiation (30), modulation of p53 activity (21), and formation of subnuclear domains (31,32). Several lncRNAs were found to recruit RNA binding proteins and affect histone modifications, with immediate ramifications on gene regulation (33,34).…”

Section: Significancementioning

confidence: 99%

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Doose¹,

Haake

Bernhart³

et al. 2015

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

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Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.MYC | lncRNA | cell cycle | B-cell lymphoma M YC is a transcription factor belonging to the basic helixloop-helix zipper family that was originally identified in Burkitt lymphoma (BL) because of a chromosomal translocation that juxtaposes the MYC oncogene with one of three immunoglobulin (Ig) loci (1-3). In BL, the deregulation of the oncogenic transcription factor MYC is considered to be the major driving force in lymphoma development (4, 5). MYC overexpression is not restricted to BL and has been found to be a common feature SignificanceGains of the MYC gene are the most common imbalances in cancer and are associated with poor prognosis, particularly in B-cell lymphoma. Recent advances in DNA sequencing have revealed the existence of thousands of long noncoding RNAs (lncRNAs) with unknown functional relevance. We have here identified a MYC-regulated lncRNA that we named MYC-induced long noncoding RNA (MINCR) that has a strong correlation with MYC expression in cancer. We show that MINCR is functional and controls cell cycle progression by influencing the expression of MYC-regulated cell cycle genes. MINCR is, therefore, a novel player in MYC's transcriptional network, with the potential to open new therapeutic windows in the fight against malignant lymphoma and, possibly, all cancers that rely on MYC expression.

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Section: Significancementioning

confidence: 99%

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Doose¹,

Haake

Bernhart³

et al. 2015

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

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“…1; Brown et al 1991b;Lee et al 1996;Simmler et al 1996;Willard 1996;Chureau et al 2002). Known as the Xic, the region has been genetically delineated to a <500-kb region, with a 100-to 200-kb subregion being sufficient to recapitulate many if not all steps of the inactivation process (Lee et al 1996(Lee et al , 1999bHeard et al 1999;Migeon et al 1999). At least seven distinct genes that make large ncRNAs have been identified within the Xic and surrounding regions, and several have been ascribed specific function during XCI.…”

Section: X-inactivation Checkpoints and Ncrnamentioning

confidence: 99%

Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome

Lee¹

2009

Genes Dev.

Self Cite

324

265

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Transcriptome studies are revealing that the eukaryotic genome actively transcribes a diverse repertoire of large noncoding RNAs (ncRNAs), many of which are unannotated and distinct from the small RNAs that have garnered much attention in recent years. Why are they so pervasive, and do they have a function? X-chromosome inactivation (XCI) is a classic epigenetic phenomenon associated with many large ncRNAs. Here, I provide a perspective on how XCI is achieved in mice and suggest how this knowledge can be applied to the rest of the genome. Emerging data indicate that long ncRNAs can function as guides and tethers, and may be the molecules of choice for epigenetic regulation: First, unlike proteins and small RNAs, large ncRNAs remain tethered to the site of transcription, and can therefore uniquely direct allelic regulation. Second, ncRNAs command a much larger sequence space than proteins, and can therefore achieve very precise spatiotemporal control of development. These properties imply that long noncoding transcripts may ultimately rival small RNAs and proteins in their versatility as epigenetic regulators, particularly for locus- and allele-specific control.

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“…The elements that identify the presence of an X chromosome in the cell are either located within the Xic or are closely associated with the Xic (Lee et al, 1999;Monkhorst et al, 2008). At the onset of X inactivation, a physical interaction of the two X chromosomes along the Xic regions has been observed (Bacher et al, 2006;Xu et al, 2006).…”

Section: Regulation Of the X Inactivation Processmentioning

confidence: 99%

Mechanistic concepts in X inactivation underlying dosage compensation in mammals

Leeb

Wutz

2010

Heredity

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Mammals inactivate one of the two female X chromosomes to compensate for the unequal copy number of X-linked genes between males and females. This process of X inactivation entails the silencing of one X chromosome in a developmentally regulated manner. In this work, we review recent findings in X inactivation and discuss how these advance the mechanistic understanding. Recent results provide an insight how the cell counts and chooses the appropriate number of X chromosomes to inactivate, how chromosome-wide gene repression is coordinated and how a stable inactive X chromosome is established. Key components of this complex regulatory system have now been identified and provide entry points for understanding epigenetic regulation in mammals. A majority of the data has been obtained from studying mice. It is presently not clear how general these findings can be applied to other mammalian species. We try to assess this aspect from data, which has become available.

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Genetic analysis of the mouse X inactivation center defines an 80-kb multifunction domain

Cited by 110 publications

References 41 publications

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Lessons from X-chromosome inactivation: long ncRNA as guides and tethers to the epigenome

Mechanistic concepts in X inactivation underlying dosage compensation in mammals

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