[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.
Centre de recherche :
ULHPC - University of Luxembourg: High Performance Computing
Disciplines :
Biochimie, biophysique & biologie moléculaire
Auteur, co-auteur :
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)
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
Organisme subsidiant :
Fonds National de la Recherche Luxembourg Fondation du Pélican de Mie et Pierre Hippert-Faber Luxembourg Rotary Foundation Deutsche Forschungsgemeinschaft
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