Fate erasure logic of gene networks underlying direct neuronal conversion of somatic cells by microRNAs

Area of Science:

• Cellular reprogramming
• Neuroscience
• Molecular biology

Background:

• MicroRNAs (miRNAs) are key regulators of gene expression.
• Neurogenic miRNAs, specifically miR-9/9*-124, can directly reprogram fibroblasts into neurons.
• The broader applicability of miR-9/9*-124 in reprogramming diverse somatic cell types is not well understood.

Purpose of the Study:

• To investigate if miR-9/9*-124 can induce neuronal conversion in cell types beyond fibroblasts.
• To elucidate the gene network erasure mechanisms employed by miR-9/9*-124 across different somatic cells.
• To identify regulators that antagonize somatic fate erasure and explore their role in neurogenesis.

Main Methods:

• Utilized miR-9/9*-124 for direct reprogramming of dura fibroblasts, astrocytes, smooth muscle cells, and pericytes.
• Analyzed cell-type-specific and pan-somatic gene expression changes, focusing on cell cycle, morphology, and proteostasis networks.
• Employed computational prediction to identify upstream regulators of somatic fate erasure.
• Investigated the effect of TP53 (p53) inhibition on neuronal conversion efficiency.

Main Results:

• miR-9/9*-124 successfully induced neuronal conversion in dura fibroblasts, astrocytes, smooth muscle cells, and pericytes.
• Identified conserved gene network erasure patterns (cell cycle, morphology, proteostasis) induced by miR-9/9*-124 across cell types.
• TP53 (p53) was identified as a key regulator antagonizing somatic fate erasure.
• Inhibition of p53 significantly enhanced neuronal conversion, even in post-mitotic cells.

Conclusions:

• miR-9/9*-124-mediated reprogramming is applicable to a broader range of somatic cells.
• miR-9/9*-124 induces a conserved pan-somatic gene network erasure logic.
• p53 inhibition is a potent enhancer of miR-9/9*-124-driven neurogenic reprogramming.