Genome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia

Trimarchi, Thomas; Bilal, Erhan; Ntziachristos, Panagiotis; Fabbri, Giulia; Dalla‐Favera, Riccardo; Tsirigos, Aristotelis; Aifantis, Iannis

doi:10.1016/j.cell.2014.05.049

Cited by 391 publications

(356 citation statements)

References 72 publications

(94 reference statements)

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“…lncRNAs have been described to be able to regulate gene expression of neighboring genes (48,49). We, therefore, asked if the expression of the most proximal genes upstream and downstream from MINCR were changed after MINCR knockdown.…”

Section: Mincr Regulates Cell Cycle Progression By Controlling the Exmentioning

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: Mincr Regulates Cell Cycle Progression By Controlling the Exmentioning

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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“…22,23 Differential expression analysis of lincRNAs in ALL patients compared to healthy controls revealed 197 lincRNAs were differentially expressed (Table S4). Among them, 104 lincRNAs were upregulated and 93 were downregulated in ALL.…”

Section: Differential Expression Of Transcripts With Epigenetic Regulmentioning

confidence: 99%

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

et al. 2015

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Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children under the age of 15. In addition to genetic aberrations, epigenetic modifications such as DNA methylation are altered in cancer and impact gene expression. To identify epigenetic alterations in ALL, genome-wide methylation profiles were generated using the methylated CpG island recovery assay followed by next-generation sequencing. More than 25,000 differentially methylated regions (DMR) were observed in ALL patients with »90% present within intronic or intergenic regions. To determine the regulatory potential of the DMR, whole-transcriptome analysis was performed and integrated with methylation data. Aberrant promoter methylation was associated with the altered expression of genes involved in transcriptional regulation, apoptosis, and proliferation. Novel enhancer-like sequences were identified within intronic and intergenic DMR. Aberrant methylation in these regions was associated with the altered expression of neighboring genes involved in cell cycle processes, lymphocyte activation and apoptosis. These genes include potential epi-driver genes, such as SYNE1, PTPRS, PAWR, HDAC9, RGCC, MCOLN2, LYN, TRAF3, FLT1, and MELK, which may provide a selective advantage to leukemic cells. In addition, the differential expression of epigenetic modifier genes, pseudogenes, and non-coding RNAs was also observed accentuating the role of erroneous epigenetic gene regulation in ALL.

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“…Although heritable changes in gene regulation that occur via modification of the DNA without changes to the DNA sequence are often referred to as epigenetic programming, noncoding RNA (ncRNA)-mediated transcriptional or posttranscriptional regulation is one of the major regulation mechanisms for epigenetic programming (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Recent studies have identified thousands of long ncRNAs (lncRNAs) (17,23) in mammalian genomes that regulate gene expression in a variety of immunological processes (31)(32)(33)(34)(35), such as differentiation of T cells (33,36) and dendritic cells (DCs) (35).…”

Section: T Uberculosis (Tb) Caused By Mycobacterium Tuberculosis (Mtb)mentioning

confidence: 99%

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 ⁺ T-cell immune responses in tuberculosis infection

Wang

Zhong

Xie

et al. 2015

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

172

160

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Molecular mechanisms for T-cell immune responses modulated by T cell-inhibitory molecules during tuberculosis (TB) infection remain unclear. Here, we show that active human TB infection up-regulates CD244 and CD244 signaling-associated molecules in CD8 + T cells and that blockade of CD244 signaling enhances production of IFN-γ and TNF-α. CD244 expression/signaling in TB correlates with high levels of a long noncoding RNA (lncRNA)-BC050410 [named as lncRNA-AS-GSTT1(1-72) or lncRNA-CD244] in the CD244 + CD8 + T-cell subpopulation. CD244 signaling drives lncRNA-CD244 expression via sustaining a permissive chromatin state in the lncRNA-CD244 locus. By recruiting polycomb protein enhancer of zeste homolog 2 (EZH2) to infg/tnfa promoters, lncRNA-CD244 mediates H3K27 trimethylation at infg/tnfa loci toward repressive chromatin states and inhibits IFN-γ/TNF-α expression in CD8 + T cells. Such inhibition can be reversed by knock down of lncRNA-CD244. Interestingly, adoptive transfer of lncRNA-CD244-depressed CD8 + T cells to Mycobacterium tuberculosis (MTB)-infected mice reduced MTB infection and TB pathology compared with lncRNA-CD244-expressed controls. Thus, this work uncovers previously unidentified mechanisms in which T cell-inhibitory signaling and lncRNAs regulate T-cell responses and host defense against TB infection.tuberculosis | lncRNA | CD8 + T cells

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Genome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia

Cited by 391 publications

References 72 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

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 ⁺ T-cell immune responses in tuberculosis infection

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Genome-wide Mapping and Characterization of Notch-Regulated Long Noncoding RNAs in Acute Leukemia

Cited by 391 publications

References 72 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

Integrated methylome and transcriptome analysis reveals novel regulatory elements in pediatric acute lymphoblastic leukemia

Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 + T-cell immune responses in tuberculosis infection

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Long noncoding RNA derived from CD244 signaling epigenetically controls CD8 ⁺ T-cell immune responses in tuberculosis infection