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Machine learning sequence prioritization for cell type-specific enhancer design

Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations within heterogeneous tissue. Available approaches for engineering-targeted technologies for new neuron subtypes are low yield, involving intensive transgenic st...

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Detalles Bibliográficos
Autores principales: Lawler, Alyssa J, Ramamurthy, Easwaran, Brown, Ashley R, Shin, Naomi, Kim, Yeonju, Toong, Noelle, Kaplow, Irene M, Wirthlin, Morgan, Zhang, Xiaoyu, Phan, BaDoi N, Fox, Grant A, Wade, Kirsten, He, Jing, Ozturk, Bilge Esin, Byrne, Leah C, Stauffer, William R, Fish, Kenneth N, Pfenning, Andreas R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9110026/
https://www.ncbi.nlm.nih.gov/pubmed/35576146
http://dx.doi.org/10.7554/eLife.69571
Descripción
Sumario:Recent discoveries of extreme cellular diversity in the brain warrant rapid development of technologies to access specific cell populations within heterogeneous tissue. Available approaches for engineering-targeted technologies for new neuron subtypes are low yield, involving intensive transgenic strain or virus screening. Here, we present Specific Nuclear-Anchored Independent Labeling (SNAIL), an improved virus-based strategy for cell labeling and nuclear isolation from heterogeneous tissue. SNAIL works by leveraging machine learning and other computational approaches to identify DNA sequence features that confer cell type-specific gene activation and then make a probe that drives an affinity purification-compatible reporter gene. As a proof of concept, we designed and validated two novel SNAIL probes that target parvalbumin-expressing (PV+) neurons. Nuclear isolation using SNAIL in wild-type mice is sufficient to capture characteristic open chromatin features of PV+ neurons in the cortex, striatum, and external globus pallidus. The SNAIL framework also has high utility for multispecies cell probe engineering; expression from a mouse PV+ SNAIL enhancer sequence was enriched in PV+ neurons of the macaque cortex. Expansion of this technology has broad applications in cell type-specific observation, manipulation, and therapeutics across species and disease models.