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

Borja Gomez Ramos; Jochen Ohnmacht; Nikola de Lange; Aurelien Ginolhac; Elena Valceschini; Aleksandar Rakovic; Rashi Halder; Francois Massart; Christine Klein; Roland Krause; Marcel H. Schulz; Thomas Sauter; Rejko Krüger; Lasse Sinkkonen

doi:/10.1101/2023.01.27.52589

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

Borja Gomez Ramos, Jochen Ohnmacht, Nikola de Lange, Aurelien Ginolhac, Elena Valceschini, Aleksandar Rakovic, Rashi Halder, Francois Massart, Christine Klein, Roland Krause, Marcel H. Schulz, Thomas Sauter, Rejko Krüger, Lasse Sinkkonen^*

^*Corresponding author for this work

Research output: Working paper › Preprint

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.

Original language	English
Pages	2023-2021
Number of pages	3
DOIs	https://doi.org//10.1101/2023.01.27.52589
Publication status	Published - 27 Jan 2023

Publication series

Name	bioRxiv
Publisher	Cold Spring Harbor Laboratory Press

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Gomez Ramos, B., Ohnmacht, J., de Lange, N., Ginolhac, A., Valceschini, E., Rakovic, A., Halder, R., Massart, F., Klein, C., Krause, R., Schulz, M. H., Sauter, T., Krüger, R., & Sinkkonen, L. (2023). Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation. (pp. 2023-2021). (bioRxiv). https://doi.org//10.1101/2023.01.27.52589

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abstract = "Midbrain dopaminergic neurons (mDANs) control voluntary movement, cognition, and reward behavior under physiological conditions and are implicated in human diseases such as Parkinson{\textquoteright}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.",

author = "{Gomez Ramos}, Borja and Jochen Ohnmacht and {de Lange}, Nikola and Aurelien Ginolhac and Elena Valceschini and Aleksandar Rakovic and Rashi Halder and Francois Massart and Christine Klein and Roland Krause and Schulz, {Marcel H.} and Thomas Sauter and Rejko Kr{\"u}ger and Lasse Sinkkonen",

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doi = "/10.1101/2023.01.27.52589",

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Gomez Ramos, B, Ohnmacht, J, de Lange, N, Ginolhac, A, Valceschini, E, Rakovic, A, Halder, R, Massart, F, Klein, C, Krause, R, Schulz, MH, Sauter, T, Krüger, R & Sinkkonen, L 2023 'Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation' bioRxiv, pp. 2023-2021. https://doi.org//10.1101/2023.01.27.52589

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T1 - Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

AU - Gomez Ramos, Borja

AU - Ohnmacht, Jochen

AU - de Lange, Nikola

AU - Ginolhac, Aurelien

AU - Valceschini, Elena

AU - Rakovic, Aleksandar

AU - Halder, Rashi

AU - Massart, Francois

AU - Klein, Christine

AU - Krause, Roland

AU - Schulz, Marcel H.

AU - Sauter, Thomas

AU - Krüger, Rejko

AU - Sinkkonen, Lasse

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N2 - 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.

AB - 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.

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

ER -

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

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