Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

Borja Gomez Ramos, Jochen Ohnmacht, Nikola de Lange, Elena Valceschini, Aurélien Ginolhac, Marie Catillon, Daniele Ferrante, Aleksandar Rakovic, Rashi Halder, François Massart, Giuseppe Arena, Paul Antony, Silvia Bolognin, Christine Klein, Roland Krause, Marcel H Schulz, Thomas Sauter, Rejko Krüger, Lasse Sinkkonen*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson's disease (PD). Many transcription factors (TFs) controlling human mDAN differentiation during development have been described, but much of the regulatory landscape remains undefined. Using a tyrosine hydroxylase (TH) human iPSC reporter line, we here generate time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicts novel regulators of mDAN differentiation and super-enhancers are used to identify key TFs. We find LBX1, NHLH1 and NR2F1/2 to promote mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. A more detailed investigation of TF targets reveals that NHLH1 promotes the induction of neuronal miR-124, LBX1 regulates cholesterol biosynthesis, and NR2F1/2 controls neuronal activity.

Original languageEnglish
Pages (from-to)254-285
Number of pages32
JournalEMBO Reports
Volume25
Issue number1
DOIs
Publication statusPublished - Jan 2024

Keywords

  • Humans
  • Dopaminergic Neurons/metabolism
  • Multiomics
  • Mesencephalon
  • Transcription Factors/genetics
  • Induced Pluripotent Stem Cells/metabolism
  • Cell Differentiation/genetics
  • Basic Helix-Loop-Helix Transcription Factors/genetics

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