Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

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) iPSC reporter line, we have generated time series transcriptomic and epigenomic profiles of purified mDANs during differentiation. Integrative analysis predicted novel central regulators of mDAN differentiation and super-enhancers were used to prioritize key TFs. We find LBX1, NHLH1 and NR2F1/2 to be necessary for mDAN differentiation and show that overexpression of either LBX1 or NHLH1 can also improve mDAN specification. NHLH1 is necessary for the induction of neuronal miR-124, while LBX1 regulates cholesterol biosynthesis, possibly through mTOR signaling. Consistently, rapamycin treatment led to an inhibition of mDAN differentiation. Thus, our work reveals novel regulators of human mDAN differentiation.

Methylome-wide and meQTL analysis helps to distinguish treatment response from non-response and pathogenesis markers in schizophrenia

“…A comprehensive understanding of the extent of differences between responder and non-responder DNA methylomes is necessary to depict treatment response heterogeneity accurately. The most significant probe identified in the study was localized to LBX1 , a transcription factor encoding gene that is essential for GABAergic differentiation in the dorsal spinal cord ( 62 ) and midbrain dopaminergic neuron specification, potentially through the regulation of cholesterol biosynthesis ( 63 ). Another significant probe was localized to A2BP1 , which is a schizophrenia risk gene and reported to have a reduced expression in the cortical regions of schizophrenia patients ( 64 ) and genetic association with olanzapine-induced weight gain in the Chinese Han population ( 65 ), suggesting its involvement in both pathogenesis and treatment response.…”