Tet3 regulates cellular identity and DNA methylation in neural progenitor cells

Santiago, Mafalda; Antunes, Cláudia; Guedes, Marta; Iacovino, Michelina; Kyba, Michael; Reik, Wolf; Sousa, Nuno; Pinto, Luísa; Branco, Miguel R.; Marques, C. Joana

doi:10.1007/s00018-019-03335-7

Cited by 33 publications

(23 citation statements)

References 68 publications

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“…TET3 protein is predominantly cytoplasmic distributed in Mash1marked GBCs of the NC mice (Fig 5J), consistent with its distributing in cytoplasm of neural precursor cells (Santiago et al, 2020), whereas as products of TET3, 5mC and 5hmC are mainly located in the nuclei and express mostly to the OSN layers. Furthermore, no staining of 5hmC in the miR-200b/a KD mice is observed in basal MOE (Fig 5N), in line with previous studies that the 5hmC is mainly labeled with the post-mitotic neural cells (Globisch et al, 2010;Szulwach et al, 2011;Mellen et al, 2012;Hahn et al, 2013;Diotel et al, 2017).…”

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confidence: 70%

The micro RNA / TET 3/ REST axis is required for olfactory globose basal cell proliferation and male behavior

Yang

Zhou

et al. 2020

EMBO Reports

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In the main olfactory epithelium (MOE), new olfactory sensory neurons (OSNs) are persistently generated to replace lost neurons throughout an organism's lifespan. This process predominantly depends on the proliferation of globose basal cells (GBCs), the actively dividing stem cells in the MOE. Here, by using CRISPR/Cas9 and RNAi coupled with adeno‐associated virus (AAV) nose delivery approaches, we demonstrated that knockdown of miR‐200b/a in the MOE resulted in supernumerary Mash1‐marked GBCs and decreased numbers of differentiated OSNs, accompanied by abrogation of male behaviors. We further showed that in the MOE, miR‐200b/a targets the ten‐eleven translocation methylcytosine dioxygenase TET3, which cooperates with RE1‐silencing transcription factor (REST) to exert their functions. Deficiencies including proliferation, differentiation, and behaviors illustrated in miR‐200b/a knockdown mice were rescued by suppressing either TET3 or REST. Our work describes a mechanism of coordination of GBC proliferation and differentiation in the MOE and olfactory male behaviors through miR‐200/TET3/REST signaling.

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confidence: 70%

The micro RNA / TET 3/ REST axis is required for olfactory globose basal cell proliferation and male behavior

Yang

Zhou

et al. 2020

EMBO Reports

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“…The TET enzymes (TET1, TET2, and TET3) catalyze the conversion of 5-mC to 5-hmC and promote DNA demethylation. The TET enzymes family are Fe 2+ and 2-oxoglutarate-dependent dioxygenases, and TET1 and TET3 contain a CXXC zinc nger domain at their amino-terminus, which is known to bind CpG sequences (45). Our results suggest that TET1 plays a key role in mediating the hypermethylation level of the p27 promoter.…”

Section: Discussionmentioning

confidence: 68%

MiR-190 Promotes Malignant Transformation and Progression of Human Urothelial Cells through CDKN1B Inhibition

Huang

Hua

Kuang

et al. 2021

Preprint

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BackgroundAlthough miR-190 has been reported to be related to human diseases, especially in the development and progression of cancer, its expression in human bladder cancer (BC) and potential contribution to BC remain unexplored. MethodsqRT-PCR was used to verify the expression level of miR-190 and CDKN1B. Flow cytometry (FCM) assays were performed to detect cell cycle. Soft agar assay was used to measure anchorage-independent growth ability. Methylation-Specific PCR, Dual-luciferase reporter assay and Western blotting were used to elucidate the potential mechanisms involved. ResultsOur studies revealed that downregulation of the CDKN1B/p27 protein is an important event related to miR-190, promoting the malignant transformation of bladder epithelial cells. miR-190 binds directly to CDKN1B 3’-UTR and destabilizes CDKN1B mRNA. Moreover, miR-190 downregulates TET1 by binding to the TET1 CDS region, which mediates hypermethylation of the CDKN1B promoter, thereby resulting in the downregulation of CDKN1B mRNA. These two aspects led to miR-190 inhibition of p27 protein expression in human BC cells. However, the increased expression of miR-190 in BC and its upstream regulatory mechanism remain unclear. A more in-depth mechanistic study showed that c-Jun promotes the transcription of Talin2, the host gene of miR-190, thus upregulating the expression of miR-190 in human BC cells. ConclusionIn this study, we found that miR-190 plays an important role in the development of BC. Taken together, these findings indicate that miR-190 may promote the malignant transformation of human urothelial cells by downregulating CDKN1B, which strengthens our understanding of miR-190 in regulating BC cell transformation.

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“…Tet3 knockdown was performed as described in [28]. Briefly, shRNA-mir cassettes for the Tet3 gene were amplified from pSM2 retroviral vectors containing the shRNAmir sequences (Open Biosystems) and cloned into the p2Lox vector using HindII and NotI restriction sites.…”

Section: Tet3 Knockdownmentioning

confidence: 99%

TET3 controls the expression of the H3K27me3 demethylase Kdm6b during neural commitment

Montibus

Cercy

Bouschet

et al. 2020

Cell. Mol. Life Sci.

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The acquisition of cell identity is associated with developmentally regulated changes in the cellular histone methylation signatures. For instance, commitment to neural differentiation relies on the tightly controlled gain or loss of H3K27me3, a hallmark of polycomb-mediated transcriptional gene silencing, at specific gene sets. The KDM6B demethylase, which removes H3K27me3 marks at defined promoters and enhancers, is a key factor in neurogenesis. Therefore, to better understand the epigenetic regulation of neural fate acquisition, it is important to determine how Kdm6b expression is regulated. Here, we investigated the molecular mechanisms involved in the induction of Kdm6b expression upon neural commitment of mouse embryonic stem cells. We found that the increase in Kdm6b expression is linked to a rearrangement between two 3D configurations defined by the promoter contact with two different regions in the Kdm6b locus. This is associated with changes in 5hydroxymethylcytosine (5hmC) levels at these two regions, and requires a functional teneleven-translocation (TET) 3 protein. Altogether, our data support a model whereby Kdm6b induction upon neural commitment relies on an intronic enhancer the activity of which is defined by its TET3-mediated 5-hmC level. This original observation reveals an unexpected interplay between the 5-hmC and H3K27me3 pathways during neural lineage commitment in mammals. It also questions to which extent KDM6B-mediated changes in H3K27me3 level account for the TET-mediated effects on gene expression.

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Tet3 regulates cellular identity and DNA methylation in neural progenitor cells

Cited by 33 publications

References 68 publications

The micro RNA / TET 3/ REST axis is required for olfactory globose basal cell proliferation and male behavior

The micro RNA / TET 3/ REST axis is required for olfactory globose basal cell proliferation and male behavior

MiR-190 Promotes Malignant Transformation and Progression of Human Urothelial Cells through CDKN1B Inhibition

TET3 controls the expression of the H3K27me3 demethylase Kdm6b during neural commitment

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