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Cortical organoids reveal human-specific role of METTL5 in neurodevelopment via regulation of CHCHD2

ABSTRACT: METTL5 catalyzes N6-methyladenosine (m6A) modification on 18S rRNA. In humans, loss-of-function mutations in METTL5 cause severe microcephaly and intellectual disability, whereas Mettl5 knockout (KO) animal models display inconsistent and incomplete microcephaly phenotypes. To better model human disease, we generated METTL5-KO human induced pluripotent stem cell (hiPSC)-derived cortical organoids, which exhibited impaired neural progenitor cell (NPC) proliferation and differentiation, leading to reduced ventricle-like structures and more faithful recapitulation of patient phenotypes. Mechanistically, Ribo-seq analysis revealed broad translational changes in METTL5-KO NPCs consistent with cellular stress responses rather than transcript-specific translational changes. Single-cell RNA-seq identified downregulation of CHCHD2, a mitochondrial regulator of oxidative metabolism. Reintroduction of CHCHD2 in METTL5-KO NPCs rescued proliferation and partially rescued oxidative metabolism defects. This suggests dysregulation of CHCHD2 is a driver of METTL5-mediated regulation of neurogenesis. These findings highlight a previously uncharacterized link between METTL5, CHCHD2, and cellular metabolism as essential for proper human brain development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328362 | GEO | 2026/06/10

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE328362_METTL5_KO_WT_RNAseq_DESeq2_results.csv.gz	Csv
	GSE328362_METTL5_KO_WT_TE_Ribolog_results.csv.gz	Csv
	GSE328362_METTL5_KO_WT_rna_rpf_raw_transcript_counts.csv.gz	Csv

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Cortical organoids reveal human-specific role of METTL5 in neurodevelopment via regulation of CHCHD2 [scRNA-seq]

Project description:METTL5 catalyzes N6-methyladenosine (m6A) modification on 18S rRNA. In humans, loss-of-function mutations in METTL5 cause severe microcephaly and intellectual disability, whereas Mettl5 knockout (KO) animal models display inconsistent and incomplete microcephaly phenotypes. To better model human disease, we generated METTL5-KO human induced pluripotent stem cell (hiPSC)-derived cortical organoids, which exhibited impaired neural progenitor cell (NPC) proliferation and differentiation, leading to reduced ventricle-like structures and more faithful recapitulation of patient phenotypes. Mechanistically, Ribo-seq analysis revealed broad translational changes in METTL5-KO NPCs consistent with cellular stress responses rather than transcript-specific translational changes. Single-cell RNA-seq identified downregulation of CHCHD2, a mitochondrial regulator of oxidative metabolism. Reintroduction of CHCHD2 in METTL5-KO NPCs rescued proliferation and partially rescued oxidative metabolism defects. This suggests dysregulation of CHCHD2 is a driver of METTL5-mediated regulation of neurogenesis. These findings highlight a previously uncharacterized link between METTL5, CHCHD2, and cellular metabolism as essential for proper human brain development.

2026-06-10 | GSE334981 | GEO

Mapping translation in wild-type and METTL5 knockout (KO) mice

Project description:We performed ribosome profiling on wild-type and METTL5 KO mice to investigate translation changes due to loss of METTL5.

2021-11-19 | GSE188798 | GEO

Mapping translation in wild-type and METTL5 knockout (KO) HepG2 cells

Project description:We performed ribosome profiling on wild-type and METTL5 KO HepG2 cells to investigate translation changes due to loss of METTL5.

2021-05-19 | GSE174419 | GEO

Transcriptomic analysis of wild-type (WT) and METTL5 knockout (KO) mice

Project description:We report the application of next-generation sequencing to analyze the transcriptomes of brains and livers of WT and METTL5 KO mice to understand the role(s) of METTL5 in these organs.

2021-05-19 | GSE174418 | GEO

Resolving METTL5 Specificity: Direct RNA Sequencing Reveals No Evidence for METTL5 mediated mRNA m6A Methylation in mESCs

Project description:The methyltransferase-like 5 (METTL5) has been shown to catalyze m6A deposition on 18S ribosomal RNA. However, whether it also methylates mRNAs remains unclear. To address this, we employed direct RNA sequencing (ONT) for m6A detection on native mRNA molecules. We first validated the quantitative detection of m6A by ONT by treating mESCs with a METTL3 inhibitor. We then compared methylation levels of m6A sites between Mettl5-KO and WT mESCs. Our analysis provides no compelling evidence for METTL5 mediated mRNA methylation in vivo, indicating that its activity is restricted to rRNA.

2026-05-19 | GSE328291 | GEO

Mapping N6-methyladenosine (m6A) peaks in wild-type and METTL5 knockout (KO) HeLa cells

Project description:We report the application of MeRIP-seq to map m6A peaks in wild type and METTL5 KO HeLa cells to investigate targets of the m6A methyltransferase METTL5.

2021-05-19 | GSE174420 | GEO

METTL5 Blockade Enhances Anti-Tumor Immune Response via Inducing Neoantigen Generation

Project description:Tumor neoantigens play a pivotal role in immunotherapy through eliciting tumor-specific immune responses. However, their clinical application is limited by the restricted repertoire of naturally occurring neoantigens, which undergoes continuous immune editing within the tumor microenvironment. To address this critical challenge, we explored translational regulation as a reversible and safer strategy to augment neoantigen production. Through systematic analysis of translational regulatory factors associated with immunotherapy response, we identified METTL5 as a key modulator of anti-tumor immunity. METTL5 depletion in syngeneic tumor models demonstrated significant enhancement of endogenous anti-tumor immunity across distinct MHC-I haplotypes, with synergistic effects observed when combined with immune checkpoint blockade. Based on evolutionary conservation of ribosomal decoding center modifications and established mechanisms from prokaryotic studies, we propose that METTL5-mediated m6A modification at the small ribosomal subunit decoding center may contribute to translational fidelity regulation. Mechanistically, integrated MHC-I immunoprecipitation-mass spectrometry and ribosome profiling revealed the identification of non-canonical peptides, including those derived from novel unannotated open reading frames (nuORFs), which provide previously absent neoantigen sources for tumor cells. T-cell receptor sequencing further demonstrated significantly enhanced clonal diversity and tumor-specific reactivity of infiltrating T cells in METTL5-deficient tumors. Therapeutic vaccination strategies targeting METTL5-deficiency-induced neoantigens, including both peptide-based and mRNA vaccines, exhibited partial anti-tumor efficacy in murine tumor models. This study establishes METTL5 as a critical translational regulator that restricts neoantigen diversity and proposes a novel combinatorial strategy to enhance immunotherapy through translational control.

2026-02-18 | GSE299761 | GEO

Loss of m6A methyltransferase METTL5 promotes cardiac hypertrophy through translational control of SUZ12

Project description:The methyltransferase-like5 (METTL5), which catalyzes m6A in 18S rRNA at position A1832, has been shown to regulate the efficient of mRNA translation in the differentiation of ES cell and the growth of cancer cells. It remains unknown that whether and how METTL5 regulates cardiac hypertrophy. In this study, we generated a mouse model (METTL5-cKO) with cardiac-specific abolishment of METTL5 in vivo. Loss function of METTL5 promotes pressure overload-induced cardiomyocyte hypertrophy and adverse remodeling. The regulatory function of METTL5 in hypertrophic growth of cardiomyocyte were further confirmed with both gain- and loss-of-function approaches in primary isolated cardiomyocytes. Mechanically, METTL5 was identified to modulate the mRNA translation of SUZ12, a core component of PRC2 complex, and further regulate the transcriptome shift during cardiac hypertrophy. Therefore, our study uncover an important translational regulator of cardiac hypertrophy.

2022-02-13 | GSE186615 | GEO

Function and Mechanism of METTL5-mediated translation in multiple myeloma

Project description:The abnormal expression of m6A methyltransferase is a significant factor in the occurrence and progression of tumors. The 18S ribosomal RNA (rRNA) m6A methyltransferase Methyltransferase-like 5 (METTL5) is upregulated in various cancers, leading to adverse prognosis by abnormally regulating protein translation in tumor cells. However, the functionality and molecular mechanisms of METTL5 in the progression of multiple myeloma (MM) remains unknown. In this study, we demonstrate that the expression of METTL5 in the bone marrow (BM) of newly diagnosed MM patients is significantly higher than in healthy individuals and patients in remission following treatment. Importantly, we found that MM patients with upregulated METTL5 expression had a poorer prognosis. Additionally, we show that METTL5 plays a key role in promoting MM progression both in vitro and in a orthotopical xenograft model. Mechanistically, the depletion of METTL5 expression mediates a decrease in overall translation efficiency and selenium metabolism-related signaling pathway levels. We further revealed that the reduction in selenophosphate synthetase 2 (SEPHS2) translation efficiency mediated by METTL5 depletion can lead to diminished synthesis of selenoprotein and lead to increased reactive oxygen species (ROS), thereby inducing apoptosis in MM. Salvianolic Acid C (SAC) was identified as a potential METTL5 inhibitor, demonstrating significant pro-apoptotic effects during the treatment of MM both in vitro and in vivo. In summary, our research highlights the critical role of METTL5 in the progression of MM cells. Our data indicate METTL5’s function is to influence the overall translation efficiency and reprogram selenium metabolism to inhibit apoptosis.

2025-08-06 | GSE294608 | GEO

The 18S rRNA m6A methyltransferase METTL5 promotes mouse embryonic stem cell differentiation

Project description:Input mRNAs and ribosome protected fragments (RPFs) from wildtype and Mettl5 knockout (KO) mESC cells were analyzed by TruSeq Ribo Profile (Illumina) library preparation and high throughput sequencing

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