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M6A Modification Regulates Planarian Regeneration [MeRIP-seq]

ABSTRACT: The fundamental of regeneration process of invertebrates involves the renewal, differentiation and reprogramming of stem cell in an orchestrated manner. It has been known that N6-methyladenosine (m6A) regulates stem cell renewal and differentiation. It is still unclear if m6A is crucial for the regeneration at whole-organism level. Here, we demonstrate that wtap knockdown mediated m6A depletion impairs planarian regeneration upon amputation. The cell cycle related genes displayed decreased m6A while increased expression levels in response to wtap knockdown. The m6A depletion induced phenotypes can be rescued by double-knocking down these genes together with wtap, suggesting that m6A-mediated cell cycle controls planarian regeneration. Further analysis combining the single-cell sequencing unveils a unique neuronal progenitor-like cell type, named NCC and characterized by specific expression of grn, which is indispensable for neuroregeneration. Overall, our study uncovered an essential role of wtap-mediated m6A modification in regulating stem cell population dynamics and homeostasis in terms of general-body regeneration.

ORGANISM(S): Schmidtea mediterranea

PROVIDER: GSE171249 | GEO | 2023/04/28

REPOSITORIES: GEO

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m6A Modification Regulates Planarian Regeneration [RNA-seq]

Project description:The fundamental of regeneration process of invertebrates involves the renewal, differentiation and reprogramming of stem cell in an orchestrated manner. It has been known that N6-methyladenosine (m6A) regulates stem cell renewal and differentiation. It is still unclear if m6A is crucial for the regeneration at whole-organism level. Here, we demonstrate that wtap knockdown mediated m6A depletion impairs planarian regeneration upon amputation. The cell cycle related genes displayed decreased m6A while increased expression levels in response to wtap knockdown. The m6A depletion induced phenotypes can be rescued by double-knocking down these genes together with wtap, suggesting that m6A-mediated cell cycle controls planarian regeneration. Further analysis combining the single-cell sequencing unveils a unique neuronal progenitor-like cell type, named NCC and characterized by specific expression of grn, which is indispensable for neuroregeneration. Overall, our study uncovered an essential role of wtap-mediated m6A modification in regulating stem cell population dynamics and homeostasis in terms of general-body regeneration.

2023-04-28 | GSE171247 | GEO

m6A Modification Regulates Planarian Regeneration [scRNA-seq]

Project description:Regeneration is the regrowth of damaged tissues or organs, a vital mechanism in response to damages from primitive organisms to higher mammals. Planarian possesses active whole-body regenerative capability owning to its vast reservoir of adult stem cells, neoblasts, providing an ideal model to delineate the underlying mechanisms for regeneration. RNA N6-methyladenosine (m6A) modification participates in many biological processes, including stem cell self-renewal and differentiation, in particular the regeneration of hematopoietic stem cells and axons. However, how m6A controls regeneration at the whole-organism level remains largely unknown. Here, we demonstrate that the depletion of m6A methyltransferase regulatory subunit wtap abolishes planarian regeneration, potentially through regulating genes related to cell-cell communication and cell cycle. Single-cell RNA-seq (scRNA-seq) analysis unveils that the wtap knockdown induces a unique type of neural progenitor-like cells (NP-like cells), characterized by specific expression of the cell-cell communication ligand grn. Intriguingly, the depletion of m6A-modified transcripts grn/cdk9 (or cdk7) axis rescues the defective regeneration of planarian caused by wtap knockdown. Overall, our study reveals an indispensable role of m6A modification in regulating whole-organism regeneration.

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A novel RNA m6A modulator Zc3h13 plays an anchor role in facilitating nuclear RNA methylation and mouse embryonic stem cell self-renewal

Project description:N6-methyladenosine (m6A) is an abundant modification in eukaryotic mRNA, regulating mRNA dynamics by influencing mRNA stability, splicing, export and translation. Recent studies discovered m6A methyltransferases (?writer?), demethylases (?eraser?) and binding proteins (?reader?), which modulate m6A methylation. However, the precise m6A regulating machinery still remains incompletely understood. Here we demonstrate that ZC3H13, a zinc finger protein, plays an essential role in modulating m6A methylation on polyadenylated RNA in the nucleus. ZC3H13 exists in an evolutionary-conserved macromolecular complex containing WTAP, Virilizer and Hakai. We confirm the interaction among those proteins and demonstrate that knockdown of Zc3h13 in mouse embryonic stem cell (mESC) significantly decreases global m6A level on mRNA, mainly at 3? untranslated regions (3? UTR). Interestingly, fractionation assays show that upon Zc3h13 knockdown a great majority of WTAP, Virilizer and Hakai translocate to the cytoplasm and the nuclear presence of the methyltransferase Mettl3 and Mettl14 also decrease significantly. In contrast, knockdown of WTAP, Virilizer or Hakai does not change the nuclear localization of Zc3h13. This suggests that Zc3h13 is required for nuclear localization of the Zc3h13-WTAP-Virilizer-Hakai complex, which is important for RNA m6A methylation. Finally, Zc3h13 depletion, as does WTAP, Virilizer or Hakai, impairs self-renewal and triggers mESC differentiation. Taken together, our findings demonstrate that Zc3h13 plays an essential role in anchoring WTAP, Virilizer and Hakai in the nucleus to facilitate m6A methylation and to regulate mESC self-renewal.

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LC-MS/MS analysis of co-immunoprecipitation products of METTL3

Project description:N6-methyladenosine (m6A) methylation of mRNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms’ tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the mechanism of MTC assembly remains elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3), that is highly expressed in breast cancer. Furthermore, we find that both METTL3a and full-length METTL3 are required for MTC assembly, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is required for METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC assembly. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A methylation, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Consequently, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component for MTC assembly, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

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m6A Modification Promotes Planarian Regeneration

Project description:m6A Modification Promotes Planarian Regeneration

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Methylated RNA immunoprecipitation sequencing in the Kasumi-1 cell line transfected with WTAP shRNA or scramble control shRNA

Project description:To evaluate the role of WTAP in modulating the m6A abundance, we conducted m6A sequencing in the Kasumi-1 cell line transfected with a lentivirus-mediated short hairpin RNA (shRNA) targeting WTAP gene or a scramble control shRNA.

2022-09-28 | GSE214225 | GEO

Conserved functional antagonism between CELF and MBNL proteins regulates stem cell-specific alternative splicing and regeneration in planarians

Project description:Understanding gene regulation in stem cells is key to understanding stem cell biology. Contrary to transcriptional regulation the function of alternative splicing (AS) in stem cells is poorly understood. Here we study function and mechanisms of AS in a powerful in vivo model for stem cell biology, the planarian S. mediterranea. Knockdown of AS factors, computational analyses of massive RNA-sequencing data, phenotyping, and biochemical binding assays revealed a stem cell specific AS program comprising hundreds of alternative exons, intron retention events, and microexons. The conserved AS factors CELF/MBNL are main regulators of this program. We show that they antagonize each other by directly promoting or repressing stem cell specific AS events. Knockdown of CELF/MBNL leads to defective regeneration by affecting self-renewal and differentiation, respectively. Thus, AS is of key importance for stem cell regulation in vivo and antagonistic regulation by CELF/MBNL is likely an ancestral feature of animal stem cells. mRNA profiles of various samples of planarian cells, including control and knockdowns of key splicing factors in whole worms, and FACS-purified fractions

2016-08-01 | E-GEOD-75594 | biostudies-arrayexpress

Profiling of N6-methyladenosine in HepG2 cells: SETD2, METTL3, METTL14 or WTAP knockdown and control cells

Project description:SETD2 is the specific methyltransferase of H3K36me3, while METTL3, METTL14 and WTAP are the components of m6A methyltransferase complex. To understand the global effect of H3K36me3 on m6A modification, we compared the m6A profiling in SETD2 and METTL3, METTL14 or WTAP knockdown HepG2 cells, and found depletion of H3K36me3 by SETD2 silencing globally reduced m6A in human transcriptome. What’s more, most of the SETD2-dependent hypomethylation sites also responded to knockdown of METTL3, METTL14, or WTAP.

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454 Life Sciences/Roche and Illumina sequencing of small RNAs from planarian samples

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