Retinoic Acid Receptors Recognize the Mouse Genome through Binding Elements with Diverse Spacing and Topology

Moutier, Emmanuel; Ye, Tao; Choukrallah, Mohamed-Amin; Urban, Sylvia; Osz, Judith; Chatagnon, Amandine; Delacroix, Laurence; Langer, Diana; Rochel, Natacha; Moras, Dino; Galand, Benoît; Davidson, Irwin

doi:10.1074/jbc.m112.361790

Cited by 146 publications

(172 citation statements)

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“…S4). Underneath the apex of this peak, we discovered an inverted repeat consistent with IR0-type RAR elements (RAREs) (34,35). This IR0 element is highly conserved throughout eutherian mammals, including all four major superorders (Fig.…”

Section: Resultsmentioning

confidence: 85%

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Hore

Meyenn

Ravichandran

et al. 2016

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

151

139

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Epigenetic memory, in particular DNA methylation, is established during development in differentiating cells and must be erased to create naïve (induced) pluripotent stem cells. The ten-eleven translocation (TET) enzymes can catalyze the oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized derivatives, thereby actively removing this memory. Nevertheless, the mechanism by which the TET enzymes are regulated, and the extent to which they can be manipulated, are poorly understood. Here we report that retinoic acid (RA) or retinol (vitamin A) and ascorbate (vitamin C) act as modulators of TET levels and activity. RA or retinol enhances 5hmC production in naïve embryonic stem cells by activation of TET2 and TET3 transcription, whereas ascorbate potentiates TET activity and 5hmC production through enhanced Fe 2+ recycling, and not as a cofactor as reported previously. We find that both ascorbate and RA or retinol promote the derivation of induced pluripotent stem cells synergistically and enhance the erasure of epigenetic memory. This mechanistic insight has significance for the development of cell treatments for regenenerative medicine, and enhances our understanding of how intrinsic and extrinsic signals shape the epigenome.

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Section: Resultsmentioning

confidence: 85%

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Hore

Meyenn

Ravichandran

et al. 2016

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

151

139

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“…As both receptors have essentially the same DNA recognition site (RGKTCA), a canonical retinoic acid response element (RARE) is usually two direct repeats of the recognition sequence, separated by a spacer region of variable length [68]. The use of chromatin immunoprecipitation (ChIP), however, with antibodies against RARs has demonstrated a much greater diversity of RAREs than previously appreciated, including direct repeats with no spacer [69]. There is also evidence that inverted repeats with no spacer can also the target for RARs [69].…”

Section: Interaction With Dnamentioning

confidence: 99%

“…The use of chromatin immunoprecipitation (ChIP), however, with antibodies against RARs has demonstrated a much greater diversity of RAREs than previously appreciated, including direct repeats with no spacer [69]. There is also evidence that inverted repeats with no spacer can also the target for RARs [69]. ChIP results also suggest that RA bound to receptors already on the promoter of target genes may not be representative of all of the potential targets.…”

Section: Interaction With Dnamentioning

confidence: 99%

“…The advent of chromatin immunoprecipitation (ChIP) to identify targets has begun [69,70] but in the case of the RA receptors, there are clear difficulties that must be overcome. For most targets, the RA receptors will be present on the promoter regardless of whether that promoter is transcriptionally active or not and thus interpreting the information will require additional epigenetic (ChIP) data at those sites to determine the likely transcriptional status associated with specific RAREs.…”

Section: Future Directionsmentioning

confidence: 99%

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Retinoic Acid and the Development of the Endoderm

Kelly

Drysdale

2015

JDB

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Retinoic acid (RA) is an important signaling molecule in the development of the endoderm and an important molecule in protocols used to generate endodermal cell types from stem cells. In this review, we describe the RA signaling pathway and its role in the patterning and specification of the extra embryonic endoderm and different endodermal organs. The formation of endoderm is an ancient evolutionary feature and RA signaling appears to have coevolved with the vertebrate lineage. Towards that end, we describe how RA participates in many regulatory networks required for the formation of extraembryonic structures as well as the organs of the embryo proper.

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“…RAREs are classically described as direct repeats of the hexameric motif (A/G) G(G/T) TCA separated by 1, 2, or 5 nucleotides (referred to as DR1, DR2, or DR5, respectively). [19][20][21] Recently, the recurrent motif (A/G) G(G/T) T(G/C) A, which differs from the classical consensus motif (A/G) G(G/T) TCA at position 5, with a G instead of a C, was reported from the alignment of several RAREs. 20) In a previous study, we also showed that RARα was involved in the induction of Tal2 in P19 cells after the addition of atRA and suspension culture for cell aggregation.…”

Section: Tal2mentioning

confidence: 99%

Transcriptional Regulation of <i>Tal2</i> Gene by All-<i>trans</i> Retinoic Acid (atRA) in P19 Cells

Kobayashi

Suzuki

Morikawa

et al. 2015

Biological & Pharmaceutical Bulletin

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TAL2 is a transcription factor required in the normal development of mouse brain. In a previous study, we demonstrated that the expression of Tal2 gene is induced by the complex of all-trans retinoic acid (atRA) and retinoic acid receptor α (RARα) in mouse embryonal carcinoma P19 cells. atRA is also known to be important in inducing P19 cells to differentiate into the neural lineage. Therefore, we believe that the function of TAL2 in neural differentiation may be clarified by utilizing P19 cells. As the atRA-RARα complex induced the expression of Tal2, we focused on the regulatory region that is involved in its transcription. The atRA-RARα complex occupies a characteristic retinoic acid response element (RARE) located in the promoter of target genes. Therefore, we searched for RARE on the mouse Tal2 and found that a RARE-like element was located in the intron. We also found that a TATA-box-like element was located in the 5′-region of Tal2. Involvement between transcriptional activity and the TATA-box-like element was confirmed in the luciferase assay, and TATA-box binding protein was bound to this element upstream of Tal2 in P19 cells. atRA signaling activated the transcription through the RARE-like element, and RARα was bound to this element on Tal2 in P19 cells. In addition, the interaction between these elements on Tal2 was shown in the chromatin immunoprecipitation assay. These results suggest that the transcription of Tal2 is coordinately mediated by two distal regulatory elements.Key words Tal2 gene; retinoic acid receptor α (RARα); TATA-box binding protein (TBP); retinoic acid response element (RARE); TATA-box TAL2 1,2) is a transcription factor required for the normal development of mouse brain. The expression of Tal2 gene is observed in the diencephalon, mesencephalon, and metencephalon of the developing mouse brain.3) Tal2-null mutant mice are viable at birth and initially appear normal. However, they develop signs of runting and die between 13 and 32 d after birth. 4) Therefore, Tal2 is thought to play a pivotal role in development of the brain.We found that Tal2 expression is altered in P19 cells after addition of all-trans retinoic acid (atRA) and suspension culture for cell aggregation. Moreover, we showed that its expression is induced by atRA.5) P19 cells are a line of pluripotent embryonal carcinoma and appear to differentiate into derivatives of three germ layers-endoderm, mesoderm, or ectoderm-depending on the inducers and culture conditions, using the same mechanisms as normal embryonic cells. atRA treatment and cell aggregation have an important role in the induction of neural differentiation in P19 cells.6-8) Because these cells have been used as a model in studies of neural differentiation, we believe that the function of Tal2 in development may be clarified by utilizing P19 cells.atRA, which is a metabolic product of vitamin A, is one of the most important morphogens, and is a signal molecule involved in neural differentiation. [9][10][11] atRA is also known to be capable of inducing embr...

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Retinoic Acid Receptors Recognize the Mouse Genome through Binding Elements with Diverse Spacing and Topology

Cited by 146 publications

References 44 publications

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

Retinoic Acid and the Development of the Endoderm

Transcriptional Regulation of <i>Tal2</i> Gene by All-<i>trans</i> Retinoic Acid (atRA) in P19 Cells

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