Parallel functional testing identifies enhancers active in early postnatal mouse brain

Enhancers are cis-regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type-specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput fu...

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Autores principales:	Jason T Lambert, Linda Su-Feher, Karol Cichewicz, Tracy L Warren, Iva Zdilar, Yurong Wang, Kenneth J Lim, Jessica L Haigh, Sarah J Morse, Cesar P Canales, Tyler W Stradleigh, Erika Castillo Palacios, Viktoria Haghani, Spencer D Moss, Hannah Parolini, Diana Quintero, Diwash Shrestha, Daniel Vogt, Leah C Byrne, Alex S Nord
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	enhancer MPRA neurodevelopment Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/7eac98db50864ef3b555ee122dfb4a63
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spelling	oai:doaj.org-article:7eac98db50864ef3b555ee122dfb4a632021-11-09T07:49:10ZParallel functional testing identifies enhancers active in early postnatal mouse brain10.7554/eLife.694792050-084Xe69479https://doaj.org/article/7eac98db50864ef3b555ee122dfb4a632021-10-01T00:00:00Zhttps://elifesciences.org/articles/69479https://doaj.org/toc/2050-084XEnhancers are cis-regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type-specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in the brain.Jason T LambertLinda Su-FeherKarol CichewiczTracy L WarrenIva ZdilarYurong WangKenneth J LimJessica L HaighSarah J MorseCesar P CanalesTyler W StradleighErika Castillo PalaciosViktoria HaghaniSpencer D MossHannah ParoliniDiana QuinteroDiwash ShresthaDaniel VogtLeah C ByrneAlex S NordeLife Sciences Publications LtdarticleenhancerMPRAneurodevelopmentMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	enhancer MPRA neurodevelopment Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	enhancer MPRA neurodevelopment Medicine R Science Q Biology (General) QH301-705.5 Jason T Lambert Linda Su-Feher Karol Cichewicz Tracy L Warren Iva Zdilar Yurong Wang Kenneth J Lim Jessica L Haigh Sarah J Morse Cesar P Canales Tyler W Stradleigh Erika Castillo Palacios Viktoria Haghani Spencer D Moss Hannah Parolini Diana Quintero Diwash Shrestha Daniel Vogt Leah C Byrne Alex S Nord Parallel functional testing identifies enhancers active in early postnatal mouse brain
description	Enhancers are cis-regulatory elements that play critical regulatory roles in modulating developmental transcription programs and driving cell-type-specific and context-dependent gene expression in the brain. The development of massively parallel reporter assays (MPRAs) has enabled high-throughput functional screening of candidate DNA sequences for enhancer activity. Tissue-specific screening of in vivo enhancer function at scale has the potential to greatly expand our understanding of the role of non-coding sequences in development, evolution, and disease. Here, we adapted a self-transcribing regulatory element MPRA strategy for delivery to early postnatal mouse brain via recombinant adeno-associated virus (rAAV). We identified and validated putative enhancers capable of driving reporter gene expression in mouse forebrain, including regulatory elements within an intronic CACNA1C linkage disequilibrium block associated with risk in neuropsychiatric disorder genetic studies. Paired screening and single enhancer in vivo functional testing, as we show here, represents a powerful approach towards characterizing regulatory activity of enhancers and understanding how enhancer sequences organize gene expression in the brain.
format	article
author	Jason T Lambert Linda Su-Feher Karol Cichewicz Tracy L Warren Iva Zdilar Yurong Wang Kenneth J Lim Jessica L Haigh Sarah J Morse Cesar P Canales Tyler W Stradleigh Erika Castillo Palacios Viktoria Haghani Spencer D Moss Hannah Parolini Diana Quintero Diwash Shrestha Daniel Vogt Leah C Byrne Alex S Nord
author_facet	Jason T Lambert Linda Su-Feher Karol Cichewicz Tracy L Warren Iva Zdilar Yurong Wang Kenneth J Lim Jessica L Haigh Sarah J Morse Cesar P Canales Tyler W Stradleigh Erika Castillo Palacios Viktoria Haghani Spencer D Moss Hannah Parolini Diana Quintero Diwash Shrestha Daniel Vogt Leah C Byrne Alex S Nord
author_sort	Jason T Lambert
title	Parallel functional testing identifies enhancers active in early postnatal mouse brain
title_short	Parallel functional testing identifies enhancers active in early postnatal mouse brain
title_full	Parallel functional testing identifies enhancers active in early postnatal mouse brain
title_fullStr	Parallel functional testing identifies enhancers active in early postnatal mouse brain
title_full_unstemmed	Parallel functional testing identifies enhancers active in early postnatal mouse brain
title_sort	parallel functional testing identifies enhancers active in early postnatal mouse brain
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/7eac98db50864ef3b555ee122dfb4a63
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Parallel functional testing identifies enhancers active in early postnatal mouse brain

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