Regulation of cell-type-specific transcriptomes by microRNA networks during human brain development

Nat Neurosci. 2018 Dec;21(12):1784-1792. doi: 10.1038/s41593-018-0265-3. Epub 2018 Nov 19.

Authors

Tomasz J Nowakowski^#^{1

2}, Neha Rani^#^{3

4}, Mahdi Golkaram^#⁵, Hongjun R Zhou^#^{3

6}, Beatriz Alvarado^{7

8}, Kylie Huch^{3

6}, Jay A West⁹, Anne Leyrat⁹, Alex A Pollen^{7

10}, Arnold R Kriegstein^{7

8}, Linda R Petzold^{5

11}, Kenneth S Kosik^{12

13}

Affiliations

¹ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
² Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA. tomasz.nowakowski@ucsf.edu.
³ Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, USA.
⁴ Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
⁵ Department of Mechanical Engineering, University of California, Santa Barbara, Santa Barbara, CA, USA.
⁶ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
⁷ Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA, USA.
⁸ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁹ New Technologies, Fluidigm Corporation, South San Francisco, CA, USA.
¹⁰ Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
¹¹ Department of Computer Science, University of California, Santa Barbara, Santa Barbara, CA, USA.
¹² Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, USA. kosik@lifesci.ucsb.edu.
¹³ Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA. kosik@lifesci.ucsb.edu.

^# Contributed equally.

Abstract

MicroRNAs (miRNAs) regulate many cellular events during brain development by interacting with hundreds of mRNA transcripts. However, miRNAs operate nonuniformly upon the transcriptional profile with an as yet unknown logic. Shortcomings in defining miRNA-mRNA networks include limited knowledge of in vivo miRNA targets and their abundance in single cells. By combining multiple complementary approaches, high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation with an antibody to AGO2 (AGO2-HITS-CLIP), single-cell profiling and computational analyses using bipartite and coexpression networks, we show that miRNA-mRNA interactions operate as functional modules that often correspond to cell-type identities and undergo dynamic transitions during brain development. These networks are highly dynamic during development and over the course of evolution. One such interaction is between radial-glia-enriched ORC4 and miR-2115, a great-ape-specific miRNA, which appears to control radial glia proliferation rates during human brain development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Brain / growth & development*
Brain / metabolism
Cell Proliferation
Gene Regulatory Networks*
High-Throughput Nucleotide Sequencing
Humans
MicroRNAs / metabolism*
Transcriptome*

Substances

MicroRNAs

Abstract

Publication types

MeSH terms

Substances

Grants and funding