Massively parallel techniques for cataloguing the regulome of the human brain

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

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

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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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