Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons

Abstract During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative...

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Autores principales:	Aaron M. Earley, Lena F. Burbulla, Dimitri Krainc, Rajeshwar Awatramani
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c21875a492da40c9b0c929e0d4c3f82a
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spelling	oai:doaj.org-article:c21875a492da40c9b0c929e0d4c3f82a2021-11-21T12:17:27ZIdentification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons10.1038/s41598-021-01366-42045-2322https://doaj.org/article/c21875a492da40c9b0c929e0d4c3f82a2021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01366-4https://doaj.org/toc/2045-2322Abstract During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative medicine and disease modeling. However, molecular fine tuning cell types to match their in vivo counterparts remains a challenge. Directing cell fates often result in blended or incomplete neuron identities. A better understanding of hPSC to neuron gene regulation is needed. Here, we used single cell RNA sequencing to resolve some of these graded molecular identities during human neurogenesis from hPSCs. Differentiation platforms were established to model neural induction from stem cells, and we characterized these differentiated cell types by 10x single cell RNA sequencing. Using single cell trajectory and co-expression analyses, we identified a co-regulated transcription factor module expressing achaete-scute family basic helix-loop-helix transcription factor 1 (ASCL1) and neuronal differentiation 1 (NEUROD1). We then tested the function of these transcription factors in neuron subtype differentiation by gene knockout in a novel human system that reports the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. ASCL1 was identified as a necessary transcription factor for regulating dopaminergic neurotransmitter selection.Aaron M. EarleyLena F. BurbullaDimitri KraincRajeshwar AwatramaniNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Aaron M. Earley Lena F. Burbulla Dimitri Krainc Rajeshwar Awatramani Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
description	Abstract During cellular specification, transcription factors orchestrate cellular decisions through gene regulation. By hijacking these transcriptional networks, human pluripotent stem cells (hPSCs) can be specialized into neurons with different molecular identities for the purposes of regenerative medicine and disease modeling. However, molecular fine tuning cell types to match their in vivo counterparts remains a challenge. Directing cell fates often result in blended or incomplete neuron identities. A better understanding of hPSC to neuron gene regulation is needed. Here, we used single cell RNA sequencing to resolve some of these graded molecular identities during human neurogenesis from hPSCs. Differentiation platforms were established to model neural induction from stem cells, and we characterized these differentiated cell types by 10x single cell RNA sequencing. Using single cell trajectory and co-expression analyses, we identified a co-regulated transcription factor module expressing achaete-scute family basic helix-loop-helix transcription factor 1 (ASCL1) and neuronal differentiation 1 (NEUROD1). We then tested the function of these transcription factors in neuron subtype differentiation by gene knockout in a novel human system that reports the expression of tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis. ASCL1 was identified as a necessary transcription factor for regulating dopaminergic neurotransmitter selection.
format	article
author	Aaron M. Earley Lena F. Burbulla Dimitri Krainc Rajeshwar Awatramani
author_facet	Aaron M. Earley Lena F. Burbulla Dimitri Krainc Rajeshwar Awatramani
author_sort	Aaron M. Earley
title	Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
title_short	Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
title_full	Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
title_fullStr	Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
title_full_unstemmed	Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons
title_sort	identification of ascl1 as a determinant for human ipsc-derived dopaminergic neurons
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/c21875a492da40c9b0c929e0d4c3f82a
work_keys_str_mv	AT aaronmearley identificationofascl1asadeterminantforhumanipscderiveddopaminergicneurons AT lenafburbulla identificationofascl1asadeterminantforhumanipscderiveddopaminergicneurons AT dimitrikrainc identificationofascl1asadeterminantforhumanipscderiveddopaminergicneurons AT rajeshwarawatramani identificationofascl1asadeterminantforhumanipscderiveddopaminergicneurons
_version_	1718419091871498240

Identification of ASCL1 as a determinant for human iPSC-derived dopaminergic neurons

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