Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

[en] 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.

Research center :

ULHPC - University of Luxembourg: High Performance Computing

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Gomez Ramos, Borja

Ohnmacht, Jochen

de Lange, Nikola

VALCESCHINI, Elena ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)

GINOLHAC, Aurélien ; University of Luxembourg

CATILLON, Marie ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)

FERRANTE, Daniele ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology

Rakovic, Aleksandar

HALDER, Rashi ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Sequencing Platform

Massart, François

More authors (9 more)

External co-authors :

yes

Language :

English

Title :

Multiomics analysis identifies novel facilitators of human dopaminergic neuron differentiation

Publication date :

19 December 2023

Journal title :

EMBO Reports

ISSN :

1469-221X

eISSN :

1469-3178

Publisher :

Springer Science and Business Media LLC

Volume :

Issue :

Pages :

254-285

Peer reviewed :

Peer Reviewed verified by ORBi

Focus Area :

Systems Biomedicine

Additional URL :

https://www.embopress.org/doi/epdf/10.1038/s44319-023-00024-2

FnR Project :

FNR12244779 - Molecular, Organellar And Cellular Quality Control In Parkinson’S Disease And Other Neurodegenerative Diseases, 2017 (01/05/2018-31/10/2024) - Jens Schwamborn
FNR11264123 - Ncer-pd, 2015 (01/01/2015-30/11/2020) - Rejko Krüger
FNR6682797 - Comprehensive Assessment Of Endophenotypes In Neurodegenerative Diseases - Translating Impaired Molecular Signalling Pathways Into Novel Therapeutic Strategies For Parkinson’S Disease, 2013 (01/06/2014-31/05/2019) - Rejko Krüger
FNR15850547 - Pink1-related Molecular Mechanisms To Dissect The Connection Between Type 2 Diabetes And Insulin Resistance In Parkinson’S Disease, 2021 (01/01/2022-31/08/2024) - Giuseppe Arena
FNR15839823 - Autophagy Modulation To Decrease Astrocyte Senescence In Lrrk2-g2019s Models, 2021 (01/11/2021-31/10/2023) - Silvia Bolognin

Funders :

Fonds National de la Recherche Luxembourg
Fondation du Pélican de Mie et Pierre Hippert-Faber
Luxembourg Rotary Foundation
Deutsche Forschungsgemeinschaft

Data Set :

Epigenomic analysis of human dopaminergic neuron differentiation reveals LBX1, NHLH1 and NR2F1/2 as necessary for lineage specification

Available on ORBilu :

since 02 January 2024

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