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Systematic analyses of coding and noncoding genome function in the human central nervous system

  • Author(s): Wu, David
  • Advisor(s): Weissman, Jonathan S
  • et al.
Abstract

While it is now known that human chromosomes are pervasively transcribed, the relative contribution of the coding and lncRNA genomes to cell differentiation is unknown. Using genome-wide CRISPR interference (CRISPRi) screens in human pluripotent stem cells, we systematically assessed 18,905 protein-coding and 10,678 lncRNA targets for function in neural induction, identifying 419 coding and 201 lncRNA genes that regulate this step of development. Comparative multi-omic analyses discovered broad properties of coding and lncRNA genome function, such as an enrichment of lncRNA genes for roles in differentiation rather than proliferation. In contrast, coding genes were enriched for function in cell proliferation. CRISPRi single-cell RNA-Seq (Perturb-Seq) analysis resolved differentiation phenotypes at the level of specific cellular states, revealing additional distinctions in how coding and lncRNA genes regulate neural induction. These systematic studies demonstrated key functional differences between the coding and lncRNA genomes during this critical stage of neurodevelopment.

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