METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis

Xiong, Qing; Liu, Caojie; Zheng, Xin; Zhou, Xinyi; Lei, Kexin; Zhang, Xiaohan; Wang, Qian; Lin, Weimin; Tong, Ruizhan; Xu, Ruoshi; Yuan, Quan

doi:10.1038/s41368-022-00176-2

Cited by 9 publications

(8 citation statements)

References 61 publications

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“…While WT control tongues demonstrated normal taste buds and filiform papillae across the dorsal lingual epithelium, Mettl3-eKO mice displayed severely impaired development of these features (Fig. 1E), consistent with previous work showing that loss of Mettl3 led to severe defects in taste bud development and abnormal epithelial thickening (24). More unexpectedly, however, we observed that 80% of Mettl3-eKO mice were found to have full-thickness ulcerations in the posterior aspect of the tongue, while none were present in WT controls, nor in Mettl3-heterozygotes (Krt14-Cre; Mettl3 +/fl ) (Fig.…”

Section: Loss Of Mettl3 Leads To Grossly Abnormal Epidermal and Tongu...supporting

confidence: 91%

Mettl3-catalyzed m ⁶ A regulates histone modifier and modification expression in self-renewing somatic tissue

Maldonado López,

Ko,

Huang

et al. 2023

Sci. Adv.

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N6 -methyladenosine (m 6 A) is the most abundant modification on messenger RNAs (mRNAs) and is catalyzed by methyltransferase-like protein 3 (Mettl3). To understand the role of m 6 A in a self-renewing somatic tissue, we deleted Mettl3 in epidermal progenitors in vivo. Mice lacking Mettl3 demonstrate marked features of dysfunctional development and self-renewal, including a loss of hair follicle morphogenesis and impaired cell adhesion and polarity associated with oral ulcerations. We show that Mettl3 promotes the m 6 A-mediated degradation of mRNAs encoding critical histone modifying enzymes. Depletion of Mettl3 results in the loss of m 6 A on these mRNAs and increases their expression and associated modifications, resulting in widespread gene expression abnormalities that mirror the gross phenotypic abnormalities. Collectively, these results have identified an additional layer of gene regulation within epithelial tissues, revealing an essential role for m 6 A in the regulation of chromatin modifiers, and underscoring a critical role for Mettl3-catalyzed m 6 A in proper epithelial development and self-renewal.

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Section: Loss Of Mettl3 Leads To Grossly Abnormal Epidermal and Tongu...supporting

confidence: 91%

Mettl3-catalyzed m ⁶ A regulates histone modifier and modification expression in self-renewing somatic tissue

Maldonado López,

Ko,

Huang

et al. 2023

Sci. Adv.

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show abstract

“…While WT control tongues demonstrated normal taste buds and filiform papillae across the dorsal lingual epithelium, Mettl3-eKO mice displayed severely impaired development of these features (Fig. 1E), consistent with previous work showing that loss of Mettl3 led to severe defects in taste bud development and abnormal epithelial thickening (Xiong et al 2022). More surprisingly however, we observed that 80% of Mettl3-eKO mice were found to have full thickness ulcerations in the posterior aspect of the tongue, while none were present in WT controls, nor in Mettl3-heterozygotes (Krt14-Cre; Mettl3 +/fl ) (Fig.…”

Section: Loss Of Mettl3 Leads To Grossly Abnormal Epidermal and Tongu...supporting

confidence: 91%

METTL3 maintains epithelial homeostasis through m⁶A-dependent regulation of chromatin modifiers

López

Huang

Pacella

et al. 2022

Preprint

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The balance between epithelial stemness and differentiation requires the precise regulation of gene expression programs. Epitranscriptomic RNA modifications have been implicated in both epithelial development as well as cancers. However, the underlying mechanisms are poorly understood. Here, we show that deletion of the m6A methyltransferase, METTL3, impairs the m6A-mediated degradation of numerous mRNA transcripts encoding critical chromatin modifying enzymes, resulting in widespread gene expression abnormalities as well as both aberrant cutaneous and oral epithelial phenotypes in vivo. Collectively, these results offer new insights into a new layer of gene regulation within epithelial surface tissues and will inform future epitranscriptomic studies within epithelial cancer and developmental biology.

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“…The staining was performed as previously described. [65] Sections were incubated overnight at 4 °C with primary antibodies: goat-anti-LEPR…”

Section: Methodsmentioning

confidence: 99%

Lepr‐Expressing PDLSCs Contribute to Periodontal Homeostasis and Respond to Mechanical Force by Piezo1

et al. 2023

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Periodontium supports teeth in a mechanically stimulated tissue environment, where heterogenous stem/progenitor populations contribute to periodontal homeostasis. In this study, Leptin receptor+ (Lepr+) cells are identified as a distinct periodontal ligament stem cell (PDLSC) population by single‐cell RNA sequencing and lineage tracing. These Lepr+ PDLSCs are located in the peri‐vascular niche, possessing multilineage potential and contributing to tissue repair in response to injury. Ablation of Lepr+ PDLSCs disrupts periodontal homeostasis. Hyper‐loading and unloading of occlusal forces modulate Lepr+ PDLSCs activation. Piezo1 is demonstrated that mediates the mechanosensing of Lepr+ PDLSCs by conditional Piezo1‐deficient mice. Meanwhile, Yoda1, a selective activator of Piezo1, significantly accelerates periodontal tissue growth via the induction of Lepr+ cells. In summary, Lepr marks a unique multipotent PDLSC population in vivo, to contribute toward periodontal homeostasis via Piezo1‐mediated mechanosensing.

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METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis

Cited by 9 publications

References 61 publications

Mettl3-catalyzed m ⁶ A regulates histone modifier and modification expression in self-renewing somatic tissue

Mettl3-catalyzed m ⁶ A regulates histone modifier and modification expression in self-renewing somatic tissue

METTL3 maintains epithelial homeostasis through m⁶A-dependent regulation of chromatin modifiers

Lepr‐Expressing PDLSCs Contribute to Periodontal Homeostasis and Respond to Mechanical Force by Piezo1

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METTL3-mediated m6A RNA methylation regulates dorsal lingual epithelium homeostasis

Cited by 9 publications

References 61 publications

Mettl3-catalyzed m 6 A regulates histone modifier and modification expression in self-renewing somatic tissue

Mettl3-catalyzed m 6 A regulates histone modifier and modification expression in self-renewing somatic tissue

METTL3 maintains epithelial homeostasis through m6A-dependent regulation of chromatin modifiers

Lepr‐Expressing PDLSCs Contribute to Periodontal Homeostasis and Respond to Mechanical Force by Piezo1

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Mettl3-catalyzed m ⁶ A regulates histone modifier and modification expression in self-renewing somatic tissue

Mettl3-catalyzed m ⁶ A regulates histone modifier and modification expression in self-renewing somatic tissue

METTL3 maintains epithelial homeostasis through m⁶A-dependent regulation of chromatin modifiers