Imprinted <i>Igf2r</i> silencing depends on continuous <i>Airn</i> lncRNA expression and is not restricted to a developmental window

Santoro, Federica; Mayer, Daniela; Klement, Ruth M.; Warczok, Katarzyna E.; Stukalov, Alexey; Barlow, Denise P.; Pauler, Florian M.

doi:10.1242/dev.088849

Cited by 85 publications

(56 citation statements)

References 60 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Also for the imprinted Igf2r/Airn locus, Airn antisense transcription through the Igf2r promoter is required for silencing of Igf2r (5). Studies with an inducible Airn promoter indicate that antisense Airn transcription leads to CpG methylation of the Igf2r promoter, stabilizing the silent state, which can then be maintained in the absence of Airn transcriptional read-through (43). The present findings obtained for an experimental sense-antisense gene pair in undifferentiated and differentiating ESCs, taken together with the above-described findings on physiological gene pairs, clearly demarcate a developmental time window where irreversible silencing is established.…”

Section: Discussionsupporting

confidence: 74%

Chromatin-Mediated Reversible Silencing of Sense-Antisense Gene Pairs in Embryonic Stem Cells Is Consolidated upon Differentiation

Loos

Loda

Wijk

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

Genome-wide gene expression studies have indicated that the eukaryotic genome contains many gene pairs showing overlapping sense and antisense transcription. Regulation of these coding and/or noncoding gene pairs involves intricate regulatory mechanisms. In the present study, we utilized an enhanced green fluorescent protein (EGFP)-tagged reporter plasmid cis linked to a doxycycline-inducible antisense promoter, generating antisense transcription that fully overlaps EGFP, to study the mechanism and dynamics of gene silencing after induction of noncoding antisense transcription in undifferentiated and differentiating mouse embryonic stem cells (ESCs). We found that EGFP silencing is reversible in ESCs but is locked into a stable state upon ESC differentiation. Reversible silencing in ESCs is chromatin dependent and is associated with accumulation of trimethylated lysine 36 on histone H3 (H3K36me3) at the EGFP promoter region. In differentiating ESCs, antisense transcription-induced accumulation of H3K36me3 was associated with an increase in CpG methylation at the EGFP promoter. Repression of the sense promoter was affected by small-molecule inhibitors which interfere with DNA methylation and histone demethylation pathways. Our results indicate a general mechanism for silencing of fully overlapping sense-antisense gene pairs involving antisense transcription-induced accumulation of H3K36me3 at the sense promoter, resulting in reversible silencing of the sense partner, which is stabilized during ESC differentiation by CpG methylation.

show abstract

Section: Discussionsupporting

confidence: 74%

Chromatin-Mediated Reversible Silencing of Sense-Antisense Gene Pairs in Embryonic Stem Cells Is Consolidated upon Differentiation

Loos

Loda

Wijk

et al. 2015

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…It has recently been revealed that the imprinting activity regulated by the lncRNA AIRN is a function of the local act of transcription across the locus and not mediated by the transcript itself (Latos et al 2012;Santoro et al 2013). Prior to this, it was thought to have an activity that was attributed to a functional RNA molecule.…”

Section: In Vivo Lncrna Loss Of Functionmentioning

confidence: 99%

Linking RNA biology to lncRNAs

2015

View full text Add to dashboard Cite

The regulatory potential of RNA has never ceased to amaze: from RNA catalysis, to RNA-mediated splicing, to RNA-based silencing of an entire chromosome during dosage compensation. More recently, thousands of long noncoding RNA (lncRNA) transcripts have been identified, the majority with unknown function. Thus, it is tempting to think that these lncRNAs represent a cadre of new factors that function through ribonucleic mechanisms. Some evidence points to several lncRNAs with tantalizing physiological contributions and thought-provoking molecular modalities. However, dissecting the RNA biology of lncRNAs has been difficult, and distinguishing the independent contributions of functional RNAs from underlying DNA elements, or the local act of transcription, is challenging. Here, we aim to survey the existing literature and highlight future approaches that will be needed to link the RNA-based biology and mechanisms of lncRNAs in vitro and in vivo.

show abstract

“…These results shed light on two intriguing areas: the role of MRUL in the development of GC MDR and a possible mechanism for MRUL function. lncRNAs can promote the epigenetic silencing of protein-coding genes (43,44). In contrast, lncRNAs can also possess enhancer-like functions to promote expression of neighboring proteincoding genes (40,(45)(46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA MRUL Promotes ABCB1 Expression in Multidrug-Resistant Gastric Cancer Cell Sublines

Wang

Zhang

et al. 2014

Molecular and Cellular Biology

129

View full text Add to dashboard Cite

bMultidrug resistance (MDR) is the most common cause of chemotherapy failure in gastric cancer (GC) treatment; however, the underlying molecular mechanisms remain elusive. Long noncoding RNAs (lncRNAs) can be involved in carcinogenesis, but the effects of lncRNAs on MDR are poorly understood. We show here that the lncRNA MRUL (MDR-related and upregulated lncRNA), located 400 kb downstream of ABCB1 (ATP-binding cassette, subfamily B, member 1), was significantly upregulated in two multidrug-resistant GC cell sublines, SGC7901/ADR and SGC7901/VCR. Furthermore, the relative expression levels of MRUL in GC tissues were negatively correlated with in vitro growth inhibition rates of GC specimens treated with chemotherapeutic drugs and indicated a poor prognosis for GC patients. MRUL knockdown in SGC7901/ADR and SGC7901/VCR cells led to increased rates of apoptosis, increased accumulation, and reduced doxorubicin (Adriamycin [ADR]) release in the presence of ADR or vincristine. Moreover, MRUL depletion reduced ABCB1 mRNA levels in a dose-and time-dependent manner. Heterologous luciferase reporter assays demonstrated that MRUL might positively affect ABCB1 expression in an orientation-and position-independent manner. Our findings indicate that MRUL promotes ABCB1 expression and is a potential target to reverse the MDR phenotype of GC MDR cell sublines.T he development of multidrug resistance (MDR) followed by failure to respond to chemotherapy is a crucial problem in gastric cancer (GC) (1, 2). However, to date, the molecular mechanisms underlying MDR have not been fully elucidated.Chemotherapeutic drugs, such as doxorubicin (Adriamycin [ADR]) and vincristine (VCR), can induce Bax-and Bak-mediated apoptosis of tumor cells through DNA damage. Ribosomal protein (RP) S13 (RPS13) or RPL23 can promote MDR in gastric cancer cells by suppressing drug-induced apoptosis (3), while the activation of c-Jun N-terminal kinase 1 (JNK1) and caspase 3 (CPP32) is associated with enhancement of apoptosis in Baxtransfected gastric cancer cells (4). Among the MDR-related proteins, P-glycoprotein (P-gp), a 170-kDa transmembrane glycoprotein encoded by ABCB1, has been extensively studied (5-7). P-gp is an ATP-dependent efflux pump in the ATP-binding cassette (ABC) family and is expressed constitutively in the liver, kidney, intestine, brain, and many other tissues (5, 8). P-gp exhibits broad substrate specificity and is necessary for the elimination of intracellular toxic metabolic products or materials to maintain body homeostasis. Hence, P-gp can reduce intracellular chemotherapeutic drug concentrations by transporting cytotoxic agents out of the cell. P-gp upregulation often results in a compromised chemotherapy response and a worse prognosis for malignant tumor patients. However, the mechanism by which P-gp is upregulated remains unclear.Long noncoding RNAs (lncRNAs) refer to RNAs that lack coding potential, are Ͼ200 bp in length, and are responsible for at least 80% of all genome transcripts. lncRNAs play important roles in regulating t...

show abstract

Imprinted Igf2r silencing depends on continuous Airn lncRNA expression and is not restricted to a developmental window

Cited by 85 publications

References 60 publications

Chromatin-Mediated Reversible Silencing of Sense-Antisense Gene Pairs in Embryonic Stem Cells Is Consolidated upon Differentiation

Chromatin-Mediated Reversible Silencing of Sense-Antisense Gene Pairs in Embryonic Stem Cells Is Consolidated upon Differentiation

Linking RNA biology to lncRNAs

Long Noncoding RNA MRUL Promotes ABCB1 Expression in Multidrug-Resistant Gastric Cancer Cell Sublines

Contact Info

Product

Resources

About