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Massively parallel techniques for cataloguing the regulome of the human brain

Nature Neuroscience volume 23, pages 1509–1521 (2020)Cite this article

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Abstract

Complex brain disorders are highly heritable and arise from a complex polygenic risk architecture. Many disease-associated loci are found in non-coding regions that house regulatory elements. These elements influence the transcription of target genes—many of which demonstrate cell-type-specific expression patterns—and thereby affect phenotypically relevant molecular pathways. Thus, cell-type-specificity must be considered when prioritizing candidate risk loci, variants and target genes. This Review discusses the use of high-throughput assays in human induced pluripotent stem cell-based neurodevelopmental models to probe genetic risk in a cell-type- and patient-specific manner. The application of massively parallel reporter assays in human induced pluripotent stem cells can characterize the human regulome and test the transcriptional responses of putative regulatory elements. Parallel CRISPR-based screens can further functionally dissect this genetic regulatory architecture. The integration of these emerging technologies could decode genetic risk into medically actionable information, thereby improving genetic diagnosis and identifying novel points of therapeutic intervention.

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Fig. 1: Framework for using MPRAs to characterize putative regulatory elements with cell-type specificity.
Fig. 2: hiPSCs provide a cell-type-specific and donor-dependent platform for the study of neurogenomics.
Fig. 3: Outline of the MPRA workflow.
Fig. 4: CRISPR-Cas9-based forward genetic screens.

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Acknowledgements

This work was partially supported by National Institute of Health (NIH) grants R56 MH101454 (K.J.B), R01 MH106056 (K.J.B.), R01 MH109897 (K.J.B.) and R01 MH118278 (L.M.H.). All figures in this review were created with BioRender.com

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Authors and Affiliations

  1. Graduate School of Biomedical Science, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kayla G. Townsley & Kristen J. Brennand

  2. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kayla G. Townsley & Kristen J. Brennand

  3. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kayla G. Townsley & Kristen J. Brennand

  4. Pamela Sklar Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kayla G. Townsley & Laura M. Huckins

  5. Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kristen J. Brennand

  6. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kristen J. Brennand & Laura M. Huckins

  7. Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kristen J. Brennand & Laura M. Huckins

  8. Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Kristen J. Brennand & Laura M. Huckins

  9. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Laura M. Huckins

  10. Mental Illness Research, Education and Clinical Centers, James J. Peters Department of Veterans Affairs Medical Center, Bronx, NY, USA

    Laura M. Huckins

Authors
  1. Kayla G. Townsley
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  2. Kristen J. Brennand
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  3. Laura M. Huckins
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Contributions

K.G.T., K.J.B., and L.M.H. wrote the manuscript.

Corresponding authors

Correspondence to Kristen J. Brennand or Laura M. Huckins.

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The authors declare no conflicts of interest.

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Peer review information Nature Neuroscience thanks Martin Kampmann and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Townsley, K.G., Brennand, K.J. & Huckins, L.M. Massively parallel techniques for cataloguing the regulome of the human brain. Nat Neurosci 23, 1509–1521 (2020). https://doi.org/10.1038/s41593-020-00740-1

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