Genetically encoded barcodes for correlative volume electron microscopy
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The paper introduces a new method for genetically encoding electron microscopy (EM) contrast agents called EMcapsulins. EMcapsulins are based on self-assembling protein nanocompartments called encapsulins.
By fusing different numbers (1-3) of metallothionein domains to the inner surface of encapsulins of different sizes, the authors generated 6 classes of circular barcodes that can be differentiated in EM images. The barcoded EMcapsulins provide nanometer-scale contrast that is detectable by standard EM sample preparation and imaging techniques, without needing extra steps like substrate incubation.
An automated segmentation and classification pipeline could differentiate the 6 EMcapsulin barcodes with decent accuracy. The encoding capacity was further expanded by arranging EMcapsulins into distinct patterns using rigid protein spacers. By fusing fluorescent proteins, the EMcapsulins could also be tracked by light microscopy and correlated to EM data. The fluorescent EMcapsulins could be targeted to subcellular structures like membrane proteins.
EMcapsulin expression in cultured mammalian cells, fly brains, and mouse brain tissue demonstrated their utility as multichannel EM reporters to map gene expression patterns at high resolution. Overall, this genetically encodable toolkit enables multiplexed contrast for EM connectomics and correlation of EM data with light microscopy. The approach could help augment anatomical maps with molecular information.
https://www.nature.com/articles/s41587-023-01713-y
