Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

Kitra Cates, Matthew J. McCoy, Ji Sun Kwon, Yangjian Liu, Daniel G. Abernathy, Bo Zhang, Shaopeng Liu, Paul Gontarz, Woo Kyung Kim, Shawei Chen, Wenjun Kong, Joshua N. Ho, Kyle F. Burbach, Harrison W. Gabel, Samantha A. Morris, Andrew S. Yoo

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Cell-fate conversion generally requires reprogramming effectors to both introduce fate programs of the target cell type and erase the identity of starting cell population. Here, we reveal insights into the activity of microRNAs miR-9/9 and miR-124 (miR-9/9-124) as reprogramming agents that orchestrate direct conversion of human fibroblasts into motor neurons by first eradicating fibroblast identity and promoting uniform transition to a neuronal state in sequence. We identify KLF-family transcription factors as direct target genes for miR-9/9-124 and show their repression is critical for erasing fibroblast fate. Subsequent gain of neuronal identity requires upregulation of a small nuclear RNA, RN7SK, which induces accessibilities of chromatin regions and neuronal gene activation to push cells to a neuronal state. Our study defines deterministic components in the microRNA-mediated reprogramming cascade.

Original languageEnglish
Pages (from-to)127-140.e9
JournalCell Stem Cell
Volume28
Issue number1
DOIs
StatePublished - Jan 7 2021

Keywords

  • cell fate
  • chromatin regulation
  • direct conversion
  • epigenetics
  • microRNA
  • neuronal reprogramming
  • non-coding RNA
  • single-cell RNA-sequencing

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