Combined Experimental and System-Level Analyses Reveal the Complex Regulatory Network of miR-124 during Human Neurogenesis

Non-coding RNAs regulate many biological processes including neurogenesis. The brain-enriched miR-124 has been assigned as a key player of neuronal differentiation via its complex but little understood regulation of thousands of annotated targets. To systematically chart its regulatory functions, we used CRISPR/Cas9 gene editing to disrupt all six miR-124 alleles in human induced pluripotent stem cells. Upon neuronal induction, miR-124-deleted cells underwent neurogenesis and became functional neurons, albeit with altered morphology and neurotransmitter specification. Using RNA-induced-silencing-complex precipitation, we identified 98 high-confidence miR-124 targets, of which some directly led to decreased viability. By performing advanced transcription-factor-network analysis, we identified indirect miR-124 effects on apoptosis, neuronal subtype differentiation, and the regulation of previously uncharacterized zinc finger transcription factors. Our data emphasize the need for combined experimental- and system-level analyses to comprehensively disentangle and reveal miRNA functions, including their involvement in the neurogenesis of diverse neuronal cell types found in the human brain.

Gysi, Deisy M.Free University of Berlin,Leipzig University (author)
Fallmann, JoergLeipzig University (author)
Lenk, KerstinDresden University of Technology (author)
Petri, RebeccaLund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups(Swepub:lu)med-rbp (author)
Swiersy, AnkaDresden University of Technology (author)
Klapper, Simon D.Dresden University of Technology (author)
Pircs, KarolinaLund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups(Swepub:lu)med-kpc (author)
Khattak, ShahryarDresden University of Technology (author)
Stadler, Peter F.Max Planck Institute for Mathematics in the Sciences,Leipzig University,Santa Fe Institute (author)
Jakobsson, JohanLund University,Lunds universitet,Molekylär neurogenetik,Forskargrupper vid Lunds universitet,Molecular Neurogenetics,Lund University Research Groups(Swepub:lu)mphy-jja (author)
Nowick, KatjaFree University of Berlin (author)
Busskamp, VolkerDresden University of Technology (author)
Dresden University of TechnologyFree University of Berlin (creator_code:org_t)

By the author/editor: Kutsche, Lisa K.; Gysi, Deisy M.; Fallmann, Joerg; Lenk, Kerstin; Petri, Rebecca; Swiersy, Anka; show more...; Klapper, Simon D ...; Pircs, Karolina; Khattak, Shahrya ...; Stadler, Peter F ...; Jakobsson, Johan; Nowick, Katja; Busskamp, Volker; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

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