Functional enhancer elements drive subclass-selective expression from mouse to primate neocortex.
Animals
Chromatin
/ genetics
Databases, Genetic
Dependovirus
/ genetics
Disease
/ genetics
Enhancer Elements, Genetic
Epigenesis, Genetic
Gene Expression Regulation
Genetic Vectors
/ metabolism
Genome
Humans
Mice
Neocortex
/ metabolism
Neurons
/ metabolism
Parvalbumins
/ metabolism
Primates
Species Specificity
AAVs
ATAC-seq
brain cell types
enhancers
epigenetics
ex vivo brain slice
genetic tools
human
macaque
parvalbumin
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
30 03 2021
30 03 2021
Historique:
received:
14
04
2020
revised:
07
07
2020
accepted:
25
01
2021
entrez:
31
3
2021
pubmed:
1
4
2021
medline:
27
1
2022
Statut:
ppublish
Résumé
Viral genetic tools that target specific brain cell types could transform basic neuroscience and targeted gene therapy. Here, we use comparative open chromatin analysis to identify thousands of human-neocortical-subclass-specific putative enhancers from across the genome to control gene expression in adeno-associated virus (AAV) vectors. The cellular specificity of reporter expression from enhancer-AAVs is established by molecular profiling after systemic AAV delivery in mouse. Over 30% of enhancer-AAVs produce specific expression in the targeted subclass, including both excitatory and inhibitory subclasses. We present a collection of Parvalbumin (PVALB) enhancer-AAVs that show highly enriched expression not only in cortical PVALB cells but also in some subcortical PVALB populations. Five vectors maintain PVALB-enriched expression in primate neocortex. These results demonstrate how genome-wide open chromatin data mining and cross-species AAV validation can be used to create the next generation of non-species-restricted viral genetic tools.
Identifiants
pubmed: 33789096
pii: S2211-1247(21)00067-X
doi: 10.1016/j.celrep.2021.108754
pmc: PMC8163032
mid: NIHMS1689235
pii:
doi:
Substances chimiques
Chromatin
0
Parvalbumins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
108754Subventions
Organisme : NIH HHS
ID : P51 OD010425
Pays : United States
Organisme : NIDA NIH HHS
ID : R01 DA036909
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY023277
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066509
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002319
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000423
Pays : United States
Organisme : NIMH NIH HHS
ID : RF1 MH114126
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY030441
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.K.M., L.T.G., E.E.H., H.Z., B.T., E.L., J.T.T., and B.P.L. are inventors on several U.S. patent applications related to this work. The remaining authors declare no competing interests.
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