Machine learning identification of enhancers in the rhesus macaque genome.

Journal: Neuron
Published Date: May 21, 2025

Abstract

Nonhuman primate (NHP) neuroanatomy and cognitive complexity make NHPs ideal models to study human neurobiology and disease. However, NHP circuit-function investigations are limited by the availability of molecular reagents that are effective in NHPs. This calls for reagent development approaches that prioritize NHPs. Therefore, we derived enhancers from the NHP genome. We defined cell-type-specific open chromatin regions (OCRs) in single-cell data from rhesus macaques. We trained machine-learning models to rank those OCRs according to their potential as cell-type-specific enhancers for cells in the dorsolateral prefrontal cortex (DLPFC). We packaged the top-ranked layer-3-pyramidal-neuron enhancer into AAV and injected it into the macaque DLPFC. Expression was mostly restricted to layers 2 and 3 and confirmed with light-driven activation of channelrhodopsin. These results provide a crucial tool for studying the causal functions of DLPFC and provide a roadmap for optimized gene delivery in primates.

Authors

  • Jing He
    School of Management, Guilin University of Aerospace Technology, Guilin, China.
  • BaDoi N Phan
    Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, United States.
  • Willa G Kerkhoff
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Aydin Alikaya
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Tao Hong
    ICF International, 2635 Meridian Pkwy #200, Durham, NC 27713, United States.
  • Olivia R Brull
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • J Megan Fredericks
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Morgan Sedorovitz
    Department of Ophthalmology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Chaitanya Srinivasan
    Department of Computational Biology, Carnegie Mellon University, Pittsburgh, PA, USA.
  • Michael J Leone
    Department of Neurology, Massachusetts General Hospital, Boston, MA.
  • Olivia M Wirfel
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Ashley Brown
    Computational Biology Department, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
  • Samuel Dauby
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Rachel K Tittle
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Meng K Lin
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Bryan M Hooks
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Andreea C Bostan
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Omar A Gharbawie
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
  • Leah C Byrne
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States.
  • Andreas R Pfenning
    Computational Biology Department, School of Computer Science, Carnegie Mellon University, Pittsburgh, United States.
  • William R Stauffer
    Department of Neurobiology, University of Pittsburgh, Pittsburgh, United States.

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