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TRIM28 establishes skeletal stem cell identity and safeguards skeletogenesis (Cut&Run)

ABSTRACT: The identity, renewal, and multipotency of stem cells are controlled by epigenetic mechanisms. DNA methylation and trimethylation on histone H3K9 (H3K9me3) are two epigenetic marks that coordinate gene silencing in early embryogenesis. Yet whether they also play a role in regulating somatic stem cell activities governing organogenesis, particularly in the skeletal system, is unknown. Here we show that chromatin silencing, established by TRIM28 (aka. KAP1 and TIF1β) via DNA methylation and H3K9me3 during early organogenesis is crucial for skeletal development. Loss of TRIM28 in skeletal stem cells unsilences the promoter and two previously uncharacterized enhancers of the Grem1 gene, leading to GREM1 hyperexpression, which further activates AKT/mTORC1 signaling to promote skeletal stem cell renewal while restricting osteogenesis and chondrogenesis. Notably, loss of Trim28 in the growth plate also leads to the emergence of a novel stem cell cluster with neural crest cell properties and a distinctive neurogenic tendency. These collectively result in a wide range of skeletal abnormalities. Taken together, our data suggest that TRIM28 coordinates methylation of DNA and histone H3K9 to safeguard the identity and fate determination of skeletal stem cells by epigenetically silencing the GREM1/AKT/mTORC1 signaling axis.

ORGANISM(S): Mus musculus

PROVIDER: GSE202056 | GEO | 2023/04/14

REPOSITORIES: GEO

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TRIM28 establishes skeletal stem cell identity and safeguards skeletogenesis (WGBS)

Project description:The identity, renewal, and multipotency of stem cells are controlled by epigenetic mechanisms. DNA methylation and trimethylation on histone H3K9 (H3K9me3) are two epigenetic marks that coordinate gene silencing in early embryogenesis. Yet whether they also play a role in regulating somatic stem cell activities governing organogenesis, particularly in the skeletal system, is unknown. Here we show that chromatin silencing, established by TRIM28 (aka. KAP1 and TIF1β) via DNA methylation and H3K9me3 during early organogenesis is crucial for skeletal development. Loss of TRIM28 in skeletal stem cells unsilences the promoter and two previously uncharacterized enhancers of the Grem1 gene, leading to GREM1 hyperexpression, which further activates AKT/mTORC1 signaling to promote skeletal stem cell renewal while restricting osteogenesis and chondrogenesis. Notably, loss of Trim28 in the growth plate also leads to the emergence of a novel stem cell cluster with neural crest cell properties and a distinctive neurogenic tendency. These collectively result in a wide range of skeletal abnormalities. Taken together, our data suggest that TRIM28 coordinates methylation of DNA and histone H3K9 to safeguard the identity and fate determination of skeletal stem cells by epigenetically silencing the GREM1/AKT/mTORC1 signaling axis.

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