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Impact of Mettl14 depletion on gene expression in hypothalamic neural progenitor cells [bulk RNA-seq]

ABSTRACT: m6A, the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homoeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3, or m6A reader Ythdc1, shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE289460 | GEO | 2025/03/07

REPOSITORIES: GEO

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The m6A profile of mouse hypothalamic neural progenitor cells

Project description:m6A, the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homoeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3, or m6A reader Ythdc1, shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.

2025-03-07 | GSE289463 | GEO

The m6A profile of human Arcuate nucleus-specific organoids (ARCOs)

2025-03-07 | GSE289462 | GEO

Single-cell gene expression profile of the postnatal mouse arcuate nucleus in the hypothalamus

2025-03-07 | GSE289461 | GEO

METTL14-induced m6A methylation increases G6pc biosynthesis, hepatic glucose production and metabolic disorders in obesity

Project description:RNA N6-methyladenosine (m6A) modification emerges as a pivotal mechanism underpinning numerous intracellular processes. METTL14 dimerizes with METTL3 as a m6A writer to install m6A on mRNA. Subsequently, m6A readers bind to m6A-marked RNAs to influence their metabolism/fate. However, there is a knowledge gap in m6A writers and readers governing liver metabolism. Glucose-6-phosphatase catalytic subunit (G6pc) is the gatekeeper of glycogenolysis and gluconeogenesis, determining hepatic glucose production (HGP); however, posttranscriptional regulation of G6pc is poorly understood. Here, we identify METTL14 as a posttranscriptional regulator of G6pc synthesis. Deletion of Mettl14 decreased, whereas overexpression of METTL14 increased, G6pc mRNA m6A methylation in hepatocytes. We mapped five m6A sites, and mutating the 5 sites (G6pcΔ5A) blocked METTL14-induced m6A methylation of G6pcΔ5A mRNA. METTL14 increased G6pc but not G6pcΔ5A mRNA stability and translation. YTHDF1 and YTHDF3 acted as m6A readers for G6pc mRNA to increase G6pc synthesis. Deletion of Mettl14 decreased gluconeogenesis in primary hepatocytes, liver slices, and mice. Liver METTL14, METTL3, and m6A-methylated G6pc mRNA were upregulated in mice with diet-induced obesity. Deletion of hepatic Mettl14 decreased HGP and mitigated diet-induced metabolic disorders. Collectively, these results unveil a previously-unrecognized METTL14/G6pc mRNA m6A/G6pc biosynthesis/HGP axis guiding glucose metabolism in health and disease.

2025-03-31 | GSE290887 | GEO

Temporal Control of Mammalian Cortical Neurogenesis by m6A Methylation

Project description:N6-methyladenosine (m6A), installed by the Mettl3/Mettl14 methyltransferase complex, is the most prevalent internal mRNA modification. Whether m6A regulates mammalian brain development is unknown. Here we show that Mettl14 deletion in the embryonic mouse brain diminishes m6A levels, prolongs cell cycle of radial glia cells, and extends cortical neurogenesis into postnatal stages. Mettl3 knockdown also prolongs neural progenitor cell cycle and promotes radial glia cell maintenance. m6A-sequencing of the embryonic mouse cortex reveals enrichment of mRNAs related to transcription factors, cell cycle and neuron differentiation, and Mettl14 deletion attenuates their decay. Notably, Mettl14-/- radial glia cells precociously express neuronal proteins. Further analysis uncovers previously unappreciated transcriptional pre-patterning in cortical neural stem cells. Comparison of m6A-mRNA landscapes between mouse and human cortical neural progenitors identifies human-specific tagging of transcripts related to epigenetic regulation and brain disorder risk genes. Our study reveals an epitranscriptomic mechanism in heightened transcriptional coordination during mammalian cortical neurogenesis.

2017-09-28 | GSE99017 | GEO

Structural basis of YTH domain as m6A reader

Project description:The N6-methyladenosine (m6A) is the most abundant internal modification in almost all eukaryotic messenger RNAs, and is dynamically regulated. Therefore, identification of m6A readers is especially important in determining the cellular function of m6A. YTHDF2 has recently been characterized as the first m6A reader that regulates the cytoplasmic stability of methylated RNA. Here we show that YTHDC1 is a nuclear m6A reader and report the crystal structure of the YTH domain of YTHDC1 bound to m6A-containing RNA. We further determined the structure of another YTH domain, YTHDF1, and found that the YTH domain utilizes a conserved aromatic cage to specifically recognize the methyl group of m6A. Our structural characterizations of the YTHDC1-m6A RNA complex also shed light on the molecular basis for the preferential binding of the GG(m6A)C sequence by YTHDC1 and confirm the YTH domain as a specific m6A RNA reader. PAR-CLIP (Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation) was applied to human YTHDC1 protein to identify its binding sites.

2014-09-18 | E-GEOD-58352 | biostudies-arrayexpress

m6A-RIP-seq of mRNA in yw, Mettl3, Mettl14 and Hakai flies

Project description:In order to obtain a stringent m6A methylome in Drosophila adults, we performed m6A-RIP-seq in yw control (male and female), Mettl3 (male), Mettl14 (male) and Hakai (male) mutant flies. We find that the effective m6A modification, which depends on the writer complex, is mostly distributed in 5’ UTR and near start codon in Drosophila, in contrast to the mammalian system. We define a set of high-confident m6A methylation sites shared by Mettl3, Mettl14 and Hakai, indicating that Hakai is a core component of the m6A writer complex. We also find differential methylation pattern in certain loci between male and female flies.

2021-03-01 | GSE155662 | GEO

Mettl14 is required for mouse postimplantation development by facilitating epiblast maturation

Project description:N6-methyladenosine (m6A) is the most prevalent and reversible internal modification of mammalian messenger and noncoding RNAs mediated by specificm6A writer, reader, and eraser proteins. As an m6A writer, the methyltransferase-like 3-methyltransferase–like 14 (METTL14)–Wilms tumor 1–associated protein complex dynamically regulates m6A modification and plays important roles in diverse biologic processes. However, our knowledge about the complete functions of this RNA methyltransferase complex, the contributions of each componenttothemethylation, andtheir effects on different biologicpathways are still limited. By using both in vivo and in vitro models, we here report that METTL14 is indispensable for postimplantation embryonic development by facilitating the conversion from naive to primed state of the epiblast. Depletion of Mettl14 leads to conspicuous embryonic growth retardation from embryonic d 6.5, mainly as a result of resistanceto differentiation, which further leads to embryonic lethality early in gestation. Our data highlight the critical function of METTL14 as an m6A modification regulator in orchestrating early mouse embryogenesis.

2020-12-10 | GSE162906 | GEO

Mettl14-dependent m6A modification controls iNKT cells development and function by regulating p53-dependent apoptosis pathway and TCR signaling

Project description:N6-methyladenosine (m6A) is the most common modification to mRNA in mammalian cells linked to development and disease. m6A controls CD4+ T cell homeostasis by targeting the IL-7/STAT5/SOCS family pathway and sustains Treg suppressive function. However, the role of m6A modification in non-conventional T cell development and function remains unknown. Here we showed that m6A modification was indispensable for NKT cell homeostasis using mice with T cell-specific deletion of RNA methylation writer METTL14 (T-Mettl14-/-). Loss of METTL14-dependent m6A modification led to the upregulation of p53-mediated apoptosis in double-positive (DP) thymocytes. The decreased lifespan of DP thymocytes reduced the efficiency of distal Va-Ja rearrangement, including the invariant Va14-Ja18 TCR, and therefore led to a profound decrease in the iNKT cell population. The residual iNKT cells in T-Mettl14-/- mice exhibited increased apoptosis and impaired maturation. In addition, loss of METTL14 upregulated Cish expression, which contributed to decreased proliferative response to IL-2 and IL-15 and impaired cytokine production upon TCR stimulation in METTL14-deficient iNKT cells. Furthermore, knocking down METTL14 in mature iNKT cells diminished their cytokine production, correlated with increased Cish expression and decreased TCR signaling. Collectively, our data reveals a critical role for METTL14- dependent-m6A modification in iNKT cell development and function, highlighting the need to take this effect into consideration for targeting m6A pathway in therapeutic settings.

2022-03-01 | GSE189339 | GEO

BRD4 ChIP-seq in JQ1 treatment and control in MDA-MB-231 cells.

Project description:Aberrant expression of m6A writer complex has been reported across human cancers, resulting in abnormal m6A epitranscriptome that drives tumorigenesis. But the regulatory mechanism remains unknown. Here, we identified an unappreciated interplay between the histone acetyl-lysine reader BRD4 and the m6A methyltransferase complex (MTC) across human cancers. BRD4 directly stimulates transcript expression of seven MTC subunits, allowing the maintenance of nuclear METTL3/METTL14 abundance and the formation of functional writer complex to catalyze m6A modification.

2023-12-31 | GSE219192 | GEO

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