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

doi:10.1038/s44319-023-00024-2

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

Transversal Translational Medicine

Research output: Contribution to journal › Article › Research › peer-review

2 Citations (Scopus)

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 language	English
Pages (from-to)	254-285
Number of pages	32
Journal	EMBO Reports
Volume	25
Issue number	1
DOIs	https://doi.org/10.1038/s44319-023-00024-2
Publication status	Published - 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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Gomez Ramos, B., Ohnmacht, J., de Lange, N., Valceschini, E., Ginolhac, A., Catillon, M., Ferrante, D., Rakovic, A., Halder, R., Massart, F., Arena, G., Antony, P., Bolognin, S., Klein, C., Krause, R., Schulz, M. H., Sauter, T., Krüger, R., & Sinkkonen, L. (2024). Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation. EMBO Reports, 25(1), 254-285. https://doi.org/10.1038/s44319-023-00024-2

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title = "Multiomics analysis identifies novel facilitators of human 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) 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.",

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",

author = "{Gomez Ramos}, Borja and Jochen Ohnmacht and {de Lange}, Nikola and Elena Valceschini and Aur{\'e}lien Ginolhac and Marie Catillon and Daniele Ferrante and Aleksandar Rakovic and Rashi Halder and Fran{\c c}ois Massart and Giuseppe Arena and Paul Antony and Silvia Bolognin 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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year = "2024",

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doi = "10.1038/s44319-023-00024-2",

language = "English",

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Gomez Ramos, B, Ohnmacht, J, de Lange, N, Valceschini, E, Ginolhac, A, Catillon, M, Ferrante, D, Rakovic, A, Halder, R, Massart, F, Arena, G, Antony, P, Bolognin, S, Klein, C, Krause, R, Schulz, MH, Sauter, T, Krüger, R & Sinkkonen, L 2024, 'Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation', EMBO Reports, vol. 25, no. 1, pp. 254-285. https://doi.org/10.1038/s44319-023-00024-2

TY - JOUR

T1 - Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

AU - Gomez Ramos, Borja

AU - Ohnmacht, Jochen

AU - de Lange, Nikola

AU - Valceschini, Elena

AU - Ginolhac, Aurélien

AU - Catillon, Marie

AU - Ferrante, Daniele

AU - Rakovic, Aleksandar

AU - Halder, Rashi

AU - Massart, François

AU - Arena, Giuseppe

AU - Antony, Paul

AU - Bolognin, Silvia

AU - Klein, Christine

AU - Krause, Roland

AU - Schulz, Marcel H

AU - Sauter, Thomas

AU - Krüger, Rejko

AU - Sinkkonen, Lasse

PY - 2024/1

Y1 - 2024/1

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) 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.

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) 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.

KW - Humans

KW - Dopaminergic Neurons/metabolism

KW - Multiomics

KW - Mesencephalon

KW - Transcription Factors/genetics

KW - Induced Pluripotent Stem Cells/metabolism

KW - Cell Differentiation/genetics

KW - Basic Helix-Loop-Helix Transcription Factors/genetics

UR - https://pubmed.ncbi.nlm.nih.gov/38177910

U2 - 10.1038/s44319-023-00024-2

DO - 10.1038/s44319-023-00024-2

M3 - Article

C2 - 38177910

SN - 1469-221X

VL - 25

SP - 254

EP - 285

JO - EMBO Reports

JF - EMBO Reports

IS - 1

ER -

Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

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