Expansion sequencing: Spatially precise in situ transcriptomics in intact biological systems

Science 2021 402 cites
2021:272022:482023:682024:822025:882026:89
2021 2026
402

Alon, Shahar and Goodwin, Daniel R. and Sinha, Anubhav and Wassie, Asmamaw T. and Chen, Fei and Daugharthy, Evan R. and Bando, Yosuke and Kajita, Atsushi and Xue, Andrew G. and Marrett, Karl and Prior, Robert and Cui, Yi and Payne, Andrew C. and Yao, Chun-Chen and Suk, Ho-Jun and Wang, Ru and Yu, Chih-Chieh (Jay) and Tillberg, Paul and Reginato, Paul and Pak, Nikita and Liu, Songlei and Punthambaker, Sukanya and Iyer, Eswar P. R. and Kohman, Richie E. and Miller, Jeremy A. and Lein, Ed S. and Lako, Ana and Cullen, Nicole and Rodig, Scott and Helvie, Karla and Abravanel, Daniel L. and Wagle, Nikhil and Johnson, Bruce E. and Klughammer, Johanna and Slyper, Michal and Waldman, Julia and Jan{\'e}-Valbuena, Judit and Rozenblatt-Rosen, Orit and Regev, Aviv and {IMAXT Consortium} and Church, George M. and Marblestone, Adam H. and Boyden, Edward S. and Ali, H. R. and Al Sa'd, M. and Alon, S. and Aparicio, S. and Battistoni, G. and Balasubramanian, S. and Becker, R. and Bodenmiller, B. and Boyden, E. S. and Bressan, D. and Bruna, A. and Burger, Marcel and Caldas, C. and Callari, M. and Cannell, I. G. and Casbolt, H. and Chornay, N. and Cui, Y. and Dariush, A. and Dinh, K. and Emenari, A. and Eyal-Lubling, Y. and Fan, J. and Fatemi, A. and Fisher, E. and Gonz{\'a}lez-Solares, E. A. and Gonz{\'a}lez-Fern{\'a}ndez, C. and Goodwin, D. and Greenwood, W. and Grimaldi, F. and Hannon, G. J. and Harris, O. and Harris, S. and Jauset, C. and Joyce, J. A. and Karagiannis, E. D. and Kova{\v{c}}evi{\'c}, T. and Kuett, L. and Kunes, R. and K{\"u}pc{\"u} Yolda?, A. and Lai, D. and Laks, E. and Lee, H. and Lee, M. and Lerda, G. and Li, Y. and McPherson, A. and Millar, N. and Mulvey, C. M. and Nugent, F. and O'Flanagan, C. H. and Paez-Ribes, M. and Pearsall, I. and Qosaj, F. and Roth, A. J. and Rueda, O. M. and Ruiz, T. and Sawicka, K. and Sep{\'u}lveda, L. A. and Shah, S. P. and Shea, A. and Sinha, A. and Smith, A. and Tavar{\'e}, S. and Tietscher, S. and V{\'a}zquez-Garc{\'i}a, I. and Vogl, S. L. and Walton, N. A. and Wassie, A. T. and Watson, S. S. and Weselak, J. and Wild, S. A. and Williams, E. and Windhager, J. and Whitmarsh, T. and Xia, C. and Zheng, P. and Zhuang, X.

Abstract

Methods for highly multiplexed RNA imaging are limited in spatial resolution and thus in their ability to localize transcripts to nanoscale and subcellular compartments. We adapt expansion microscopy, which physically expands biological specimens, for long-read untargeted and targeted in situ RNA sequencing. We applied untargeted expansion sequencing (ExSeq) to the mouse brain, which yielded the readout of thousands of genes, including splice variants. Targeted ExSeq yielded nanoscale-resolution maps of RNAs throughout dendrites and spines in the neurons of the mouse hippocampus, revealing patterns across multiple cell types, layer-specific cell types across the mouse visual cortex, and the organization and position-dependent states of tumor and immune cells in a human metastatic breast cancer biopsy. Thus, ExSeq enables highly multiplexed mapping of RNAs from nanoscale to system scale.

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