Machine learning sequence prioritization for cell type-specific enhancer design

Alyssa J Lawler, Easwaran Ramamurthy, Ashley R Brown, Naomi Shin, Yeonju Kim, Noelle Toong, Irene M Kaplow, Morgan Wirthlin, Xiaoyu Zhang, BaDoi N Phan, Grant A Fox, Kirsten Wade (+6 others)
<span title="2022-05-16">2022</span> <i title="eLife Sciences Publications, Ltd"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/en4qj5ijrbf5djxx7p5zzpjyoq" style="color: black;">eLife</a> </i> &nbsp;
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.
more &raquo; ... AIL 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.
<span class="external-identifiers"> <a target="_blank" rel="external noopener noreferrer" href="https://doi.org/10.7554/elife.69571">doi:10.7554/elife.69571</a> <a target="_blank" rel="external noopener" href="https://www.ncbi.nlm.nih.gov/pubmed/35576146">pmid:35576146</a> <a target="_blank" rel="external noopener" href="https://pubmed.ncbi.nlm.nih.gov/PMC9110026/">pmcid:PMC9110026</a> <a target="_blank" rel="external noopener" href="https://fatcat.wiki/release/64otkqqmhjaszjabqqomdqxiva">fatcat:64otkqqmhjaszjabqqomdqxiva</a> </span>
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