Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

Kitra Cates1, Matthew J McCoy1, Ji-Sun Kwon2, Yangjian Liu3, Daniel G Abernathy4, Bo Zhang5, Shaopeng Liu5, Paul Gontarz5, Woo Kyung Kim3, Shawei Chen3, Wenjun Kong6, Joshua N Ho4, Kyle F Burbach1, Harrison W Gabel7, Samantha A Morris8, Andrew S Yoo9

  1. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  2. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  3. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  4. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Developmental, Regenerative, and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  5. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  6. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Program in Computational and Systems Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
  7. Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, USA.
  8. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
  9. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: yooa@wustl.edu.

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.

Presented By Kitra Cates | ORCID iD

Cell & Developmental BioNicholas Liao2021-01 (Jan)