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Midbrain dopamine (mDA) neurons play a central role in reward signaling and are widely implicated in psychiatric and neurodegenerative disorders. To understand how mDA neurons perform these functions, it is important to understand how mDA-specific genes are regulated. However, cellular heterogeneity in the mammalian brain presents a major challenge to obtaining this understanding. To this end, we developed a virus-based approach to label and capture mDA nuclei for transcriptome (RNA-Seq), and low-input chromatin accessibility (liDNase-Seq) profiling, followed by predictive modeling to identify putative transcriptional regulators of mDA neurons. Using this method, we identified  Gmeb1 , a transcription factor predicted to regulate expression of  Th  and  Dat , genes critical for dopamine synthesis and reuptake, respectively.  Gmeb1  knockdown in mDA neurons resulted in downregulation of  Th  and  Dat , as well as in severe motor deficits. This study thus identifies  Gmeb1  as a master regulator of mDA gene expression and function, and provides a general method for identifying cell type-specific transcriptional regulators.

In vivo nuclear capture and molecular profiling identifies Gmeb1 as a transcriptional regulator essential for dopamine neuron function