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M6A Modification Regulates Planarian Regeneration [scRNA-seq]

ABSTRACT: 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.

ORGANISM(S): Schmidtea mediterranea

PROVIDER: GSE202928 | GEO | 2023/04/28

REPOSITORIES: GEO

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m6A Modification Regulates Planarian Regeneration [MeRIP-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 | GSE171249 | GEO

m6A Modification Regulates Planarian Regeneration [RNA-seq]

2023-04-28 | GSE171247 | GEO

Deciphering m6A dynamics at single-base level during planarian anterior-posterior (AP) axis specification [m6A]

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Deciphering m6A dynamics at single-base level during planarian anterior-posterior (AP) axis specification

Project description:Background: The establishment of the anterior-posterior (A-P) axis is a crucial step during tissue repair and regeneration. Despite the association reported recently of N6-methyladenosine (m6A) with regeneration, the mechanism underlying the regulation of m6A in A-P axis specification during regeneration remains unknown. Herein, we deciphered the m6A landscape at a single-base resolution at multiple time points during A-P axis regeneration and constructed the de novo transcriptome assembly of the Dugesia japonica planarian.

2023-09-28 | GSE216412 | GEO

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.

2023-08-18 | PXD036899 | Pride

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

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

Project description:Freshwater planarian flatworms possess uncanny regenerative capacities mediated by abundant and collectively totipotent adult stem cells. Key functions of these cells during regeneration and tissue homeostasis have been shown to depend on PIWI, a molecule required for piRNA expression in planarians. Nevertheless, the full complement of piRNAs, and microRNAs (miRNAs) in this organism has yet to be defined. Here, we report on the large scale cloning and sequencing of small RNAs from the planarian Schmidtea mediterranea, yielding altogether millions of sequenced unique small RNAs. We show that piRNAs are in part organized in genomic clusters and that they share characteristic features with mammalian and fly piRNAs. We further identify 61 novel miRNA genes and thus double the number of known planarian miRNAs. Sequencing, as well as quantitative PCR of small RNAs uncovered ten miRNAs enriched in planarian stem cells. These miRNAs are down-regulated in animals in which stem cells have been abrogated by irradiation, and thus constitute miRNAs likely associated with specific stem cell functions. Altogether, we present the first comprehensive small RNA analysis in animals belonging to the third animal superphylum, the Lophotrochozoa, and single out a number of miRNAs that may function in regeneration. Several of these miRNAs are deeply conserved in animals. Small RNAs were sequenced from FACS-sorted neoblast stem cells, untreated planarians and irradiated planarians, depleted of neoblasts

2009-06-30 | E-GEOD-16159 | biostudies-arrayexpress

High-resolution mapping reveals a conserved, widespread, dynamic meiotically regulated mRNA methylation program [Mm]

Project description:N6-methyladenosine (m6A) is a common modification of mRNA, with potential roles in fine-tuning the RNA life cycle, but little is known about the pathways regulating this process and its physiological role. Here, we used mass-spectrometry to identify a dense network of proteins physically interacting with METTL3, a core component of the methyltransferase complex, and show that two of them, WTAP and KIAA1429, are required for methylation. Combining high resolution m6A-Seq with knockdown of WTAP allowed us to define accurate maps, at near single-nucleotide resolution, of sites of mRNA methylation across four dynamic programs in human and mouse, including development, differentiation, reprogramming and immune response. Internal WTAP-dependent methylation sites were largely static across the different surveyed conditions and present in the majority of mRNAs. However, methylations were found at much lower levels within highly expressed mRNAs, and methylation is inversely correlated with mRNA stability, consistent with a role in establishing an overall basal, cell-type invariant, distribution of degradation rates. In addition, we identify thousands of WTAP-independent methylation sites at transcription initiation sites, forming part of the mRNA cap structure. We show that the methylations occur at the first transcribed nucleotide, and find that thousands of transcripts are present in different isoforms differing in the methylation state of the first transcribed nucleotide, a previously unappreciated complexity of the transcriptome. Together, our data sheds new light on the proteomic and transcriptional underpinnings of this epitranscriptomic modification in mammals. Examination of m6A methylation across different knockdowns using shRNAs in mouse embryonic fibroblasts, in embyronic and adult brains, and in dendritic cell stimulated with LPS.

2014-07-18 | E-GEOD-55575 | biostudies-arrayexpress

High-resolution mapping reveals a conserved, widespread, dynamic meiotically regulated mRNA methylation program [Hs]

Project description:N6-methyladenosine (m6A) is a common modification of mRNA, with potential roles in fine-tuning the RNA life cycle, but little is known about the pathways regulating this process and its physiological role. Here, we used mass-spectrometry to identify a dense network of proteins physically interacting with METTL3, a core component of the methyltransferase complex, and show that two of them, WTAP and KIAA1429, are required for methylation. Combining high resolution m6A-Seq with knockdown of WTAP allowed us to define accurate maps, at near single-nucleotide resolution, of sites of mRNA methylation across four dynamic programs in human and mouse, including development, differentiation, reprogramming and immune response. Internal WTAP-dependent methylation sites were largely static across the different surveyed conditions and present in the majority of mRNAs. However, methylations were found at much lower levels within highly expressed mRNAs, and methylation is inversely correlated with mRNA stability, consistent with a role in establishing an overall basal, cell-type invariant, distribution of degradation rates. In addition, we identify thousands of WTAP-independent methylation sites at transcription initiation sites, forming part of the mRNA cap structure. We show that the methylations occur at the first transcribed nucleotide, and find that thousands of transcripts are present in different isoforms differing in the methylation state of the first transcribed nucleotide, a previously unappreciated complexity of the transcriptome. Together, our data sheds new light on the proteomic and transcriptional underpinnings of this epitranscriptomic modification in mammals. Examination of m6A methylation in human Hek293 and A549 cell lines, in human embryonic stem cells (ESCs) undergoing differentiation to neural progenitor cells (NPCs), in OKMS inducible fibroblasts reprogrammed into iPSC, and upon knockdown of factors using siRNAs or shRNAs.

2014-07-18 | E-GEOD-55572 | biostudies-arrayexpress

WTAP-mediated m6A modification profiling in human nasopharyngeal carcinoma cell lines

Project description:N(6)-methyladenosine (m6A) plays an important role in the tumorigenesis and progression of cancers. However, the clinical significance of m6A and their regulatory mechanisms in nasopharyngeal carcinogenesis (NPC) remain largely unknown. In this study, we used the microarray analysis to study WTAP-mediated m6A modification profiles in human nasopharyngeal carcinoma cell line, HONE-1, by comparing 3 pairs of samples with or without WTAP knockdown.

2022-06-15 | GSE160644 | GEO

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