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Retinoic Acid-Induced DR2 Alu Transcripts in Stem Cells Generate Functional Small RNAs that Mediate Target mRNA Degradation

ABSTRACT: While liganded nuclear receptors are well established to regulate Pol II protein-coding transcription units, their role in regulation of DNA repeats remains largely unknown. Here, we report that ~2-3% of the ~1-200,000 human DR2 Alu repeats, particularly those in proximity to retinoic acid-activated Pol II transcription units, are bound and activated by retinoic acid receptor in human embryonic stem cells, triggering their Pol III-dependent transcription. The non-coding DR2 Alu transcripts are processed in a Dicer-dependent fashion into a series of small RNA products with sizes ranging ~28-65nt and exhibit substantial co-localization with P bodies. These small RNAs cause degradation of a subset of mRNAs critical for the "stem cell" state, which harbor complimentary sequences in their 3' untranslated regions. This regulation requires Ago3- dependent stabilization of full-length and processed DR2 Alu transcripts, and recruitment of Ago3-associated decapping complexes to the target mRNAs. Thus, the RAR/Pol III-dependent DR2 Alu transcriptional program in stem cells serves as a functional complement to the RAR/Pol II-dependent counterpart.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30876 | GEO | 2012/09/01

SECONDARY ACCESSION(S): PRJNA144267

REPOSITORIES: GEO

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Retinoic Acid-Induced DR2 Alu Transcripts in Stem Cells Generate Functional Small RNAs that Mediate Target mRNA Degradation

Project description:While liganded nuclear receptors are well established to regulate Pol II protein-coding transcription units, their role in regulation of DNA repeats remains largely unknown. Here, we report that ~2-3% of the ~1-200,000 human DR2 Alu repeats, particularly those in proximity to retinoic acid-activated Pol II transcription units, are bound and activated by retinoic acid receptor in human embryonic stem cells, triggering their Pol III-dependent transcription. The non-coding DR2 Alu transcripts are processed in a Dicer-dependent fashion into a series of small RNA products with sizes ranging ~28-65nt and exhibit substantial co-localization with P bodies. These small RNAs cause degradation of a subset of mRNAs critical for the "stem cell" state, which harbor complimentary sequences in their 3' untranslated regions. This regulation requires Ago3- dependent stabilization of full-length and processed DR2 Alu transcripts, and recruitment of Ago3-associated decapping complexes to the target mRNAs. Thus, the RAR/Pol III-dependent DR2 Alu transcriptional program in stem cells serves as a functional complement to the RAR/Pol II-dependent counterpart. ChIP-seq of H3K36me3 samples before and after RA (retinoic acid) treatments.

2012-09-01 | E-GEOD-30876 | biostudies-arrayexpress

DICER- andM-BM- AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation (RNA-seq)

Project description:Although liganded nuclear receptors have been established to regulate RNA polymerase II (Pol II)-dependent transcription units, their role in regulating Pol III-transcribed DNA repeats remains largely unknown. Here we report that ~2-3% of the ~100,000-200,000 total human DR2 Alu repeats located in proximity to activated Pol II transcription units are activated by the retinoic acid receptor (RAR) in human embryonic stem cells to generate Pol III-dependent RNAs. These transcripts are processed, initially in aM-BM- DICER-dependent fashion, into small RNAs (~28-65 nt) referred to as repeat-induced RNAs that cause the degradation of a subset of crucial stem-cell mRNAs, includingM-BM- NanogM-BM- mRNA, which modulate exit from the proliferative stem-cell state. This regulation requiresM-BM- AGO3-dependent accumulation of processed DR2 Alu transcripts and the subsequent recruitment ofM-BM- AGO3-associated decapping complexes to the target mRNA. In this way, the RAR-dependent and Pol III-dependent DR2 Alu transcriptional events in stem cells functionally complement the Pol II-dependent neuronal transcriptional program. RNA-sequencing of polyA selected RNA molecules in NTera2/D1 cells and Global Run On (GRO) assay followed by high throughput sequencing (GRO-seq).

2012-12-29 | E-GEOD-42563 | biostudies-arrayexpress

DICER- and AGO3-dependent generation of retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation (RNA-seq)

Project description:Although liganded nuclear receptors have been established to regulate RNA polymerase II (Pol II)-dependent transcription units, their role in regulating Pol III-transcribed DNA repeats remains largely unknown. Here we report that ~2-3% of the ~100,000-200,000 total human DR2 Alu repeats located in proximity to activated Pol II transcription units are activated by the retinoic acid receptor (RAR) in human embryonic stem cells to generate Pol III-dependent RNAs. These transcripts are processed, initially in a DICER-dependent fashion, into small RNAs (~28-65 nt) referred to as repeat-induced RNAs that cause the degradation of a subset of crucial stem-cell mRNAs, including Nanog mRNA, which modulate exit from the proliferative stem-cell state. This regulation requires AGO3-dependent accumulation of processed DR2 Alu transcripts and the subsequent recruitment of AGO3-associated decapping complexes to the target mRNA. In this way, the RAR-dependent and Pol III-dependent DR2 Alu transcriptional events in stem cells functionally complement the Pol II-dependent neuronal transcriptional program.

2012-12-29 | GSE42563 | GEO

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [ChIP-Seq]

Project description:Alu SINEs are the most numerous frequently occurring transcription units in our genomes and possess sequence competence for transcription by RNA Pol III. However, through poorly understood mechanisms, the Alu RNA levels are maintained at very low levels in normal somatic cells with obvious benefits of low rates of Alu retrotransposition and energy-economical deployment of RNA Pol III to the tRNA genes which share promoter structure and polymerase requirements with Alu SINEs. Using comparative ChIP sequencing, we unveil that a repeat binding protein, CGGBP1, binds to the transcriptional regulatory regions of Alu SINEs thereby impeding Alu transcription by inhibiting RNA Pol III recruitment. We show that this Alu-silencing depends on growth factor stimulation of cells and subsequent tyrosine phosphorylation of CGGBP1. Importantly, CGGBP1 ensures a sequence-specific discriminative inhibition of RNA Pol III activity at Alu promoters, while sparing the structurally similar tRNA promoters. Our data suggest that CGGBP1 contributes to growth-related transcription by preventing the hijacking of RNA Pol III by Alu SINEs. Examination of one DNA binding protein in two different conditions of treatment.

2015-04-29 | E-GEOD-53571 | biostudies-arrayexpress

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [ChIP-Seq]

2015-04-29 | GSE53571 | GEO

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [Affymetrix]

Project description:Alu SINEs are the most numerous frequently occurring transcription units in our genome and possess sequence competence for transcription by RNA Pol III. However, through poorly understood mechanisms, the Alu RNA levels are maintained at very low levels in normal somatic cells with obvious benefits of low rates of Alu retrotransposition and energy-economical deployment of RNA Pol III to the tRNA genes which share promoter structure and polymerase requirements with Alu SINEs. Using comparative ChIP sequencing, we unveil that a repeat binding protein, CGGBP1, binds to the transcriptional regulatory regions of Alu SINEs thereby impeding Alu transcription by inhibiting RNA Pol III recruitment. We show that this Alu-silencing depends on growth factor stimulation of cells and subsequent tyrosine phosphorylation of CGGBP1. Importantly, CGGBP1 ensures a sequence-specific discriminative inhibition of RNA Pol III activity at Alu promoters, while sparing the structurally similar tRNA promoters. Our data suggest that CGGBP1 contributes to growth-related transcription by preventing the hijacking of RNA Pol III by Alu SINEs. This study was used to find out the effect of CGGBP1 on serum-induced changes in gene expression and effect of serum on gene expression regulation by CGGBP1.

2015-12-21 | GSE54058 | GEO

Growth signals employ CGGBP1 to suppress transcription of Alu-SINEs [Affymetrix]

2015-12-21 | E-GEOD-54058 | biostudies-arrayexpress

RNA transcription and degradation of Alu retrotransposons depends on sequence features and evolutionary history

Project description:Our work sheds light on the metabolism of RNA transcripts derived from genomic Alu repeats. Since it is unclear whether Alu elements are transcribed mainly by RNA polymerase II or III, we conducted a transcription shutoff experiment and metabolic RNA labeling. We find that Alu transcripts are as stable as mRNAs and originate in part from RNA polymerase II. Furthermore, we use the de Bruijn graph of all Alu sequences to discover sequence features that match transcription factor binding motifs.

2022-04-01 | GSE185485 | GEO

Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs

Project description:The exosome-independent exoribonuclease DIS3L2 is mutated in Perlman syndrome. Here we used extensive global transcriptomic and targeted biochemical analyses to identify novel DIS3L2 substrates in human cells. We show that DIS3L2 regulates pol II transcripts, comprising selected canonical and histone-coding mRNAs, and a novel FTL_short RNA from the ferritin mRNA 5' UTR. Importantly, DIS3L2 contributes to surveillance of pre-snRNAs during their cytoplasmic maturation. Among pol III transcripts, DIS3L2 particularly targets vault and Y RNAs and an Alu-like element BC200 RNA, but not Alu repeats, which are removed by exosome-associated DIS3. Using 3' RACE-Seq, we demonstrate that all novel DIS3L2 substrates are uridylated in vivo by TUT4/TUT7 poly(U) polymerases. Uridylation-dependent DIS3L2-mediated decay can be recapitulated in vitro, thus reinforcing the tight cooperation between DIS3L2 and TUTases. Together these results indicate that catalytically inactive DIS3L2, characteristic of Perlman syndrome, can lead to deregulation of its target RNAs to disturb transcriptome homeostasis.

2016-07-19 | GSE82336 | GEO

RNA Polymerase II transcription independent of TBP (CUT&Tag)

Project description:Using CUT&Tag, a chromatin profiling technique, we show that TBP depletion via IAA surprisingly does not affect RNA Pol II transcription but affects RNA Pol III transcription. Additionally, induction of genes via heat shock and retinoic acid treatment does not require TBP. We also show that a metazoan specific paralog TRF2 does not compensate for TBP for RNA Pol II transcription and that the TFIID subunit of the Pre-initiation Complex can still form with specific subunits still binding onto DNA when TBP is depleted.

2023-04-12 | GSE206694 | GEO

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