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Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283010 | GEO | 2024/12/31

REPOSITORIES: GEO

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Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs IV

Project description:Neurogenic microRNAs 9/9* and 124 (miR-9/9*-124) drive the direct reprogramming of human fibroblasts into neurons with the initiation of the fate erasure of fibroblasts. However, whether the miR-9/9*-124 fate erasure logic extends to neuronal conversion of other somatic cell types remains unknown. Here, we uncover that miR-9/9*-124 induce neuronal conversion of multiple cell types: dura fibroblasts, astrocytes, smooth muscle cells, and pericytes. We reveal the cell type-specific and pan-somatic gene network erasure induced by miR-9/9*-124, including cell cycle, morphology, and proteostasis gene networks. Leveraging these pan-somatic gene networks, we predict upstream regulators that may antagonize somatic fate erasure. Among the predicted regulators, we identify TP53 (p53) whose inhibition is sufficient to enhance neuronal conversion even in post-mitotic cells. This study extends miR-9/9*-124 reprogramming to alternate somatic cells, reveals the pan-somatic gene network fate erasure logic of miR-9/9*-124, and shows a neurogenic role for p53-inhibition in the miR-9/9*-124-signaling cascade.

2024-12-31 | GSE283009 | GEO

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs III

2024-12-31 | GSE283008 | GEO

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs II

2024-12-31 | GSE283006 | GEO

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs I

2024-12-31 | GSE283004 | GEO

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs

Project description:Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs

| PRJNA1191437 | ENA

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs II

Project description:Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs II

| PRJNA1191441 | ENA

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs III

Project description:Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs III

| PRJNA1191442 | ENA

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs I

Project description:Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs I

| PRJNA1191440 | ENA

Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs IV

Project description:Fate Erasure Logic of Gene Networks Underlying Direct Neuronal Conversion of Somatic Cells by MicroRNAs IV

| PRJNA1191443 | ENA

MicroRNAs Overcome Cell Fate Barrier by Reducing EZH2-Controlled REST Stability during Neuronal Conversion of Human Adult Fibroblasts.

Project description:The ability to convert human somatic cells efficiently to neurons facilitates the utility of patient-derived neurons for studying neurological disorders. As such, ectopic expression of neuronal microRNAs (miRNAs), miR-9/9? and miR-124 (miR-9/9?-124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. However, how miR-9/9?-124 break the cell fate barrier to activate the neuronal program remains to be defined. Here, we identified an anti-neurogenic function of EZH2 in fibroblasts that acts outside its role as a subunit of Polycomb Repressive Complex 2 to directly methylate and stabilize REST, a transcriptional repressor of neuronal genes. During neuronal conversion, miR-9/9?-124 induced the repression of the EZH2-REST axis by downregulating USP14, accounting for the opening of chromatin regions harboring REST binding sites. Our findings underscore the interplay between miRNAs and protein stability cascade underlying the activation of neuronal program.

| S-EPMC6082428 | biostudies-literature

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