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A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex

Yao, Zizhen and Liu, Hanqing and Xie, Fangming and Fischer, Stephan and Adkins, Ricky S. and Aldrige, Andrew I. and Ament, Seth A. and Bartlett, Anna and Behrens, M. Margarita and Van den Berge, Koen and Bertagnolli, Darren and de Bezieux, Hector Roux and Biancalani, Tommaso and Booeshaghi, A. Sina and Corrada Bravo, Hector and Casper, Tamara and Colantuoni, Carlo and Crabtree, Jonathan and Creasy, Heather and Crichton, Kirsten and Crow, Megan and Dee, Nick and Dougherty, Elizabeth L. and Doyle, Wayne I. and Dudoit, Sandrine and Fang, Rongxin and Felix, Victor and Fong, Olivia and Giglio, Michelle and Goldy, Jeff and Hawrylycz, Michael and Herb, Brian R. and Hertzano, Ronna and Hou, Xiaomeng and Hu, Qiwen and Kancherla, Jayaram and Kroll, Matthew and Lathia, Kanan and Li, Yang Eric and Lucero, Jacinta D. and Luo, Chongyuan and Mahurkar, Anup and McMillen, Delissa and Nadaf, Naeem M. and Nery, Joseph R. and Nguyen, Thuc Nghi and Niu, Sheng-Yong and Ntranos, Vasilis and Orvis, Joshua and Osteen, Julia K. and Pham, Thanh and Pinto-Duarte, Antonio and Poirion, Olivier and Preissl, Sebastian and Purdom, Elizabeth and Rimorin, Christine and Risso, Davide and Rivkin, Angeline C. and Smith, Kimberly and Street, Kelly and Sulc, Josef and Svensson, Valentine and Tieu, Michael and Torkelson, Amy and Tung, Herman and Vaishnav, Eeshit Dhaval and Vanderburg, Charles R. and van Velthoven, Cindy and Wang, Xinxin and White, Owen R. and Huang, Z. Josh and Kharchenko, Peter V. and Pachter, Lior and Ngai, John and Regev, Aviv and Tasic, Bosiljka and Welch, Joshua D. and Gillis, Jesse and Macosko, Evan Z. and Ren, Bing and Ecker, Joseph R. and Zeng, Hongkui and Mukamel, Eran A. (2021) A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex. Nature, 598 (7879). pp. 103-110. ISSN 0028-0836. PMCID PMC8494649. doi:10.1038/s41586-021-03500-8. https://resolver.caltech.edu/CaltechAUTHORS:20200303-153620082

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Abstract

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigenomes from more than 500,000 individual cells in the mouse primary motor cortex, a structure that has an evolutionarily conserved role in locomotion. We developed computational and statistical methods to integrate multimodal data and quantitatively validate cell-type reproducibility. The resulting reference atlas—containing over 56 neuronal cell types that are highly replicable across analysis methods, sequencing technologies and modalities—is a comprehensive molecular and genomic account of the diverse neuronal and non-neuronal cell types in the mouse primary motor cortex. The atlas includes a population of excitatory neurons that resemble pyramidal cells in layer 4 in other cortical regions. We further discovered thousands of concordant marker genes and gene regulatory elements for these cell types. Our results highlight the complex molecular regulation of cell types in the brain and will directly enable the design of reagents to target specific cell types in the mouse primary motor cortex for functional analysis.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41586-021-03500-8DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc8494649/PubMed CentralArticle
https://doi.org/10.1101/2020.02.29.970558DOIDiscussion Paper
https://assets.nemoarchive.org/dat-ch1nqb7Related ItemBICCN MOp data
https://nemoanalytics.org/Related ItemVisualization and analysis resources
https://brainome.ucsd.edu/annoj/BICCN_MOpRelated ItemGenome browser
https://epiviz.nemoanalytics.org/biccn_mopRelated ItemEpiviz browser
https://github.com/AllenInstitute/scrattch.hicatRelated Itemscrattch.hicat
https://github.com/r3fang/SnapToolsRelated ItemSnapTools
https://github.com/lhqing/cemba_dataRelated ItemYAP and ALLCools
https://lhqing.github.io/ALLCoolsRelated Itemcemba-data.rtfd.io
https://github.com/gillislab/MetaNeighbor-BICCNRelated ItemMetaNeighbor
https://github.com/welch-lab/ligerRelated ItemLIGER
https://github.com/mukamel-lab/SingleCellFusionRelated ItemSingleCellFusion
https://github.com/kharchenkolab/conosRelated ItemConos
ORCID:
AuthorORCID
Yao, Zizhen0000-0002-9361-5607
Liu, Hanqing0000-0002-5114-6048
Xie, Fangming0000-0001-5232-1648
Fischer, Stephan0000-0002-7034-4103
Adkins, Ricky S.0000-0002-7983-5486
Aldrige, Andrew I.0000-0003-1962-8802
Ament, Seth A.0000-0001-6443-7509
Bartlett, Anna0000-0001-7059-4033
Behrens, M. Margarita0000-0002-7168-8186
Van den Berge, Koen0000-0002-1833-8478
Bertagnolli, Darren0000-0002-6626-1567
de Bezieux, Hector Roux0000-0002-1489-8339
Biancalani, Tommaso0000-0001-9104-9755
Booeshaghi, A. Sina0000-0002-6442-4502
Corrada Bravo, Hector0000-0002-1255-4444
Casper, Tamara0000-0003-1638-3651
Colantuoni, Carlo0000-0001-6818-6380
Crabtree, Jonathan0000-0002-7286-5690
Creasy, Heather0000-0002-1369-6882
Crichton, Kirsten0000-0002-7869-1492
Crow, Megan0000-0002-1172-5897
Dee, Nick0000-0002-2831-9254
Dougherty, Elizabeth L.0000-0001-8922-5078
Doyle, Wayne I.0000-0001-8276-2591
Dudoit, Sandrine0000-0002-6069-8629
Fang, Rongxin0000-0003-0107-7504
Felix, Victor0000-0002-9773-0629
Fong, Olivia0000-0002-7091-9667
Giglio, Michelle0000-0001-7628-5565
Goldy, Jeff0000-0001-5140-6922
Hawrylycz, Michael0000-0002-5741-8024
Herb, Brian R.0000-0002-5910-9647
Hertzano, Ronna0000-0002-8093-6567
Hou, Xiaomeng0000-0002-5453-9015
Hu, Qiwen0000-0003-2798-919X
Kancherla, Jayaram0000-0001-5855-5031
Kroll, Matthew0000-0002-0126-7618
Lathia, Kanan0000-0003-0080-1951
Li, Yang Eric0000-0001-6997-6018
Lucero, Jacinta D.0000-0001-7578-6624
Luo, Chongyuan0000-0002-8541-0695
Mahurkar, Anup0000-0002-4999-2296
McMillen, Delissa0000-0002-3413-4424
Nadaf, Naeem M.0000-0002-7805-8523
Nery, Joseph R.0000-0003-0153-5659
Nguyen, Thuc Nghi0000-0002-6466-5883
Niu, Sheng-Yong0000-0002-7734-1191
Ntranos, Vasilis0000-0002-2477-0670
Orvis, Joshua0000-0002-5705-5710
Osteen, Julia K.0000-0001-7058-3297
Pham, Thanh0000-0002-4738-5062
Pinto-Duarte, Antonio0000-0002-2215-7653
Poirion, Olivier0000-0002-0429-7003
Preissl, Sebastian0000-0001-8971-5616
Purdom, Elizabeth0000-0001-9455-7990
Rimorin, Christine0000-0003-1491-8552
Risso, Davide0000-0001-8508-5012
Rivkin, Angeline C.0000-0003-0399-9043
Smith, Kimberly0000-0002-3142-1970
Street, Kelly0000-0001-6379-5013
Sulc, Josef0000-0002-4928-7183
Svensson, Valentine0000-0002-9217-2330
Tieu, Michael0000-0001-9286-5623
Torkelson, Amy0000-0002-9465-4202
Tung, Herman0000-0002-0812-3318
Vaishnav, Eeshit Dhaval0000-0003-3720-8051
Vanderburg, Charles R.0000-0001-8979-5054
van Velthoven, Cindy0000-0001-5120-4546
Wang, Xinxin0000-0001-6393-2276
White, Owen R.0000-0003-2407-7320
Huang, Z. Josh0000-0003-0592-028X
Kharchenko, Peter V.0000-0002-6036-5875
Pachter, Lior0000-0002-9164-6231
Ngai, John0000-0002-1191-8971
Regev, Aviv0000-0003-3293-3158
Tasic, Bosiljka0000-0002-6861-4506
Welch, Joshua D.0000-0002-5869-2391
Gillis, Jesse0000-0002-0936-9774
Macosko, Evan Z.0000-0002-2794-5165
Ren, Bing0000-0002-5435-1127
Ecker, Joseph R.0000-0001-5799-5895
Zeng, Hongkui0000-0002-0326-5878
Mukamel, Eran A.0000-0003-3203-9535
Alternate Title:An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types
Additional Information:© 2021 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 05 March 2020; Accepted 26 March 2021; Published 06 October 2021. We are grateful to A. Bandrowski and Y. Yao for their insightful comments. This work was funded by the NIH BRAIN Initiative (U19MH114830 to H.Z., U19MH121282 to J.R.E., U19MH114821 to Z.J.H., R24MH114788 to O.R.W., U24MH114827 to M.H., R24MH114815 to R.H. and O.R.W., and NIH NIDCD DC013817 to R.H.), the Hearing Restoration project Hearing Health Foundation (R.H.) and the NIH NIGMS (GM114267 to H.C.B.). Data availability: The BICCN MOp data (RRID: SCR_015820) can be accessed via the NeMO archive (RRID: SCR_016152) at: https://assets.nemoarchive.org/dat-ch1nqb7. Visualization and analysis resources can be found at: NeMO analytics (https://nemoanalytics.org/), Genome browser (https://brainome.ucsd.edu/BICCN_MOp) and Epiviz browser (https://epiviz.nemoanalytics.org/biccn_mop). Code availability: The codes used for data analysis: scrattch.hicat (hierarchical, iterative clustering for analysis of transcriptomics) for RNA clustering (https://github.com/AllenInstitute/scrattch.hicat); SnapTools for ATAC-seq analysis (https://github.com/r3fang/SnapTools); YAP (Yet Another Pipeline) and ALLCools for DNA methylation (snmC-seq2) mapping and cluster-level aggregation (https://github.com/lhqing/cemba_data; documentation: cemba-data.rtfd.io; https://lhqing.github.io/ALLCools); MetaNeighbor for cluster reproducibility analysis (https://github.com/gillislab/MetaNeighbor-BICCN); LIGER for multimodal integration, embedding and clustering (https://github.com/welch-lab/liger); SingleCellFusion for multimodal integration, embedding and clustering (https://github.com/mukamel-lab/SingleCellFusion); Conos for cluster reproducibility analysis (https://github.com/kharchenkolab/conos); STAR v2.5.3 for RNA-seq alignment49; and Bismark for DNA methylation (snmC-seq2) alignment55. These authors contributed equally: Zizhen Yao, Hanqing Liu, Fangming Xie, Stephan Fischer. Author Contributions: A.R., A.T., B.T., C.R., C.R.V., D.B., D.M., E.L.D., E.Z.M., H.T., H.Z., J. Goldy, J.S., K.C., K.L., K. Smith, M.K., M.T., N.D., N.M.N., O.F., T.C., T.N.N. and T.P. contributed to RNA data generation. A.B., A.C.R., A.I.A., A.P.-D., C.L., H.L., J.D.L., J.K.O., J.R.E., J.R.N., M.M.B., S.-Y.N. and Y.E.L. contributed to DNA methylation (snmC-seq2) data generation. A.P.-D., B.R., J.D.L., J.K.O., M.M.B., S.P., X.H., X.W. and Y.E.L. contributed to snATAC data generation. A.M., B.R.H., C.C., C.v.V., E.A.M., F.X., H.C., H.C.B., J.C., J. Goldy, J.K., J.O., M.G., M.H., O.R.W., R.F., R.H., R.S.A., S.A.A., S.-Y.N., V.F., W.I.D. and Z.Y. contributed to data archive/infrastructure. A.R., A.S.B., B.T., D.R., E.A.M., E.D.V., E.P., E.Z.M., F.X., H.L., H.R.d.B., H.Z., J.D.W., J. Goldy, J. Gillis, J.O., K. Smith, K. Street, K.V.d.B., L.P., M.C., O.F., O.P., P.V.K., Q.H., R.F., S.D., S.F., S.-Y.N., T.B., V.N., V.S., W.I.D., Y.E.L. and Z.Y. contributed to data analysis. A.R., B.R., B.T., C.L., E.A.M., E.D.V., E.Z.M., F.X., H.L., H.Z., J.D.W., J. Gillis, J.N., M.C., M.M.B., P.V.K., Q.H., R.F., S.F., T.B., Y.E.L. and Z.Y. contributed to data interpretation. A.S.B., E.A.M., F.X., H.L., H.Z., J.D.W., J. Gillis, L.P., M.C., Q.H., S.F., Z.J.H. and Z.Y. contributed to writing the manuscript. Competing interests: B.R. is a shareholder of Arima Genomics, Inc. P.V.K. serves on the Scientific Advisory Board to Celsius Therapeutics, Inc. A.R. is an equity holder and founder of Celsius Therapeutics, an equity holder in Immunitas, and a Scientific Advisory Board member to Syros Pharmaceuticals, Neogene Therapeutics, Asimov and Thermo Fisher Scientific. Peer review information: Nature thanks Andrew Adey, Aaron D. Gitler and John Krakauer for their contribution to the peer review of this work. Peer reviewer reports are available.
Funders:
Funding AgencyGrant Number
NIHU19MH114830
NIHU19MH121282
NIHU19MH114821
NIHR24MH114788
NIHU24MH114827
NIHR24MH114815
NIHDC013817
Hearing Health FoundationUNSPECIFIED
NIHGM114267
Subject Keywords:Cellular neuroscience; Epigenomics; Gene expression profiling; Molecular neuroscience; Motor cortex
Issue or Number:7879
PubMed Central ID:PMC8494649
DOI:10.1038/s41586-021-03500-8
Record Number:CaltechAUTHORS:20200303-153620082
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200303-153620082
Official Citation:Yao, Z., Liu, H., Xie, F. et al. A transcriptomic and epigenomic cell atlas of the mouse primary motor cortex. Nature 598, 103–110 (2021). https://doi.org/10.1038/s41586-021-03500-8
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101686
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:04 Mar 2020 19:50
Last Modified:10 Jan 2022 20:44

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