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Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs

26 Pages Posted: 12 Nov 2019 Publication Status: Published

See all articles by Matthew J. McCoy

Matthew J. McCoy

Washington University in St. Louis - Department of Developmental Biology

Kitra Cates

Washington University in St. Louis - Department of Developmental Biology

Yangjian Liu

Washington University in St. Louis - Department of Developmental Biology

Daniel G. Abernathy

Washington University in St. Louis - Department of Developmental Biology

Bo Zhang

Washington University in St. Louis - Department of Developmental Biology

Shaopeng Liu

Washington University in St. Louis - Department of Developmental Biology

Paul Gontarz

Washington University in St. Louis - Department of Developmental Biology

Woo Kyung Kim

Washington University in St. Louis - Department of Developmental Biology

Shawei Chen

Washington University in St. Louis - Department of Developmental Biology

Wenjun Kong

Washington University in St. Louis - Department of Developmental Biology

Harrison W. Gabel

Washington University in St. Louis - Department of Neuroscience

Samantha A. Morris

Washington University in St. Louis - Department of Developmental Biology

Andrew Yoo

Washington University School of Medicine - Department of Developmental Biology

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Abstract

Cell-fate conversion generally presumes the activity of transcription factors to introduce fate programs of the target cell type in the midst of a pre-existing genetic network. Here, we reveal novel insights into cellular reprogramming in which microRNAs, miR-9/9* and miR-124 (miR-9/9*-124), orchestrate direct conversion of human fibroblasts by first eradicating fibroblast identity and promoting uniform transition to a neuronal state in sequence. Among the direct target genes of miR-9/9*-124, we identify KLF-family transcription factors whose repression is critical for erasing fibroblast fate. The subsequent upregulation of a small nuclear RNA, RN7SK induces chromatin reconfiguration and neuronal gene activation, pushing the reprogramming cells to a neuronal state and allowing for neuronal maturation and subtype-specification. Our study defines deterministic components in the reprogramming cascade by microRNAs.

Keywords: neuronal reprogramming, epigenetics, microRNA, single-cell RNA-sequencing, cell fate, direct conversion, non-coding RNA

Suggested Citation

McCoy, Matthew J. and Cates, Kitra and Liu, Yangjian and Abernathy, Daniel G. and Zhang, Bo and Liu, Shaopeng and Gontarz, Paul and Kim, Woo Kyung and Chen, Shawei and Kong, Wenjun and Gabel, Harrison W. and Morris, Samantha A. and Yoo, Andrew, Deconstructing Stepwise Fate Conversion of Human Fibroblasts to Neurons by MicroRNAs (November 12, 2019). Available at SSRN: https://ssrn.com/abstract=3485473 or http://dx.doi.org/10.2139/ssrn.3485473
This version of the paper has not been formally peer reviewed.

Matthew J. McCoy

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Kitra Cates

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Yangjian Liu

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Daniel G. Abernathy

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Bo Zhang

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Shaopeng Liu

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Paul Gontarz

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Woo Kyung Kim

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Shawei Chen

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Wenjun Kong

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Harrison W. Gabel

Washington University in St. Louis - Department of Neuroscience

One Brookings Drive
St. Louis, MO 63130
United States

Samantha A. Morris

Washington University in St. Louis - Department of Developmental Biology

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

Andrew Yoo (Contact Author)

Washington University School of Medicine - Department of Developmental Biology ( email )

One Brookings Drive
Campus Box 1208
St. Louis, MO 63130-4899
United States

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