Models of Global Gene Expression Define Major Domains of Cell Type and Tissue Identity

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2017 Apr 21

PMID 28426095

Citations 30

Authors

Andrew P Hutchins

Zhongzhou Yang

Yuhao Li

Fangfang He

Xiuling Fu

Xiaoshan Wang

Dongwei Li

Kairong Liu

Jiangping He

Yong Wang

Jiekai Chen

Miguel A Esteban

Duanqing Pei

Affiliations

Soon will be listed here.

Abstract

The current classification of cells in an organism is largely based on their anatomic and developmental origin. Cells types and tissues are traditionally classified into those that arise from the three embryonic germ layers, the ectoderm, mesoderm and endoderm, but this model does not take into account the organization of cell type-specific patterns of gene expression. Here, we present computational models for cell type and tissue specification derived from a collection of 921 RNA-sequencing samples from 272 distinct mouse cell types or tissues. In an unbiased fashion, this analysis accurately predicts the three known germ layers. Unexpectedly, this analysis also suggests that in total there are eight major domains of cell type-specification, corresponding to the neurectoderm, neural crest, surface ectoderm, endoderm, mesoderm, blood mesoderm, germ cells and the embryonic domain. Further, we identify putative genes responsible for specifying the domain and the cell type. This model has implications for understanding trans-lineage differentiation for stem cells, developmental cell biology and regenerative medicine.

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References

Peng G, Suo S, Chen J, Chen W, Liu C, Yu F . Spatial Transcriptome for the Molecular Annotation of Lineage Fates and Cell Identity in Mid-gastrula Mouse Embryo. Dev Cell. 2016; 36(6):681-97. DOI: 10.1016/j.devcel.2016.02.020. View

Kundaje A, Meuleman W, Ernst J, Bilenky M, Yen A, Heravi-Moussavi A . Integrative analysis of 111 reference human epigenomes. Nature. 2015; 518(7539):317-30. PMC: 4530010. DOI: 10.1038/nature14248. View

Banerji C, Miranda-Saavedra D, Severini S, Widschwendter M, Enver T, Zhou J . Cellular network entropy as the energy potential in Waddington's differentiation landscape. Sci Rep. 2013; 3:3039. PMC: 3807110. DOI: 10.1038/srep03039. View

Cahan P, Li H, Morris S, Lummertz da Rocha E, Daley G, Collins J . CellNet: network biology applied to stem cell engineering. Cell. 2014; 158(4):903-915. PMC: 4233680. DOI: 10.1016/j.cell.2014.07.020. View

Ramilowski J, Goldberg T, Harshbarger J, Kloppmann E, Kloppman E, Lizio M . A draft network of ligand-receptor-mediated multicellular signalling in human. Nat Commun. 2015; 6:7866. PMC: 4525178. DOI: 10.1038/ncomms8866. View

Morris S, Cahan P, Li H, Zhao A, San Roman A, Shivdasani R . Dissecting engineered cell types and enhancing cell fate conversion via CellNet. Cell. 2014; 158(4):889-902. PMC: 4291075. DOI: 10.1016/j.cell.2014.07.021. View

Rackham O, Firas J, Fang H, Oates M, Holmes M, Knaupp A . A predictive computational framework for direct reprogramming between human cell types. Nat Genet. 2016; 48(3):331-5. DOI: 10.1038/ng.3487. View

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

RAYMOND C, Parker E, Kettlewell J, Brown L, Page D, Kusz K . A region of human chromosome 9p required for testis development contains two genes related to known sexual regulators. Hum Mol Genet. 1999; 8(6):989-96. DOI: 10.1093/hmg/8.6.989. View

10.

Heinaniemi M, Nykter M, Kramer R, Wienecke-Baldacchino A, Sinkkonen L, Zhou J . Gene-pair expression signatures reveal lineage control. Nat Methods. 2013; 10(6):577-83. PMC: 4131748. DOI: 10.1038/nmeth.2445. View

11.

Li B, Dewey C . RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinformatics. 2011; 12:323. PMC: 3163565. DOI: 10.1186/1471-2105-12-323. View

12.

Hutchins A, Jauch R, Dyla M, Miranda-Saavedra D . glbase: a framework for combining, analyzing and displaying heterogeneous genomic and high-throughput sequencing data. Cell Regen. 2014; 3(1):1. PMC: 4230833. DOI: 10.1186/2045-9769-3-1. View

13.

Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H . The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012; 22(9):1775-89. PMC: 3431493. DOI: 10.1101/gr.132159.111. View

14.

Narendra V, Rocha P, An D, Raviram R, Skok J, Mazzoni E . CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation. Science. 2015; 347(6225):1017-21. PMC: 4428148. DOI: 10.1126/science.1262088. View

15.

Mele M, Ferreira P, Reverter F, DeLuca D, Monlong J, Sammeth M . Human genomics. The human transcriptome across tissues and individuals. Science. 2015; 348(6235):660-5. PMC: 4547472. DOI: 10.1126/science.aaa0355. View

16.

Sulston J, Schierenberg E, White J, Thomson J . The embryonic cell lineage of the nematode Caenorhabditis elegans. Dev Biol. 1983; 100(1):64-119. DOI: 10.1016/0012-1606(83)90201-4. View

17.

Edgar R, Mazor Y, Rinon A, Blumenthal J, Golan Y, Buzhor E . LifeMap Discovery™: the embryonic development, stem cells, and regenerative medicine research portal. PLoS One. 2013; 8(7):e66629. PMC: 3714290. DOI: 10.1371/journal.pone.0066629. View

18.

. A comprehensive assessment of RNA-seq accuracy, reproducibility and information content by the Sequencing Quality Control Consortium. Nat Biotechnol. 2014; 32(9):903-14. PMC: 4321899. DOI: 10.1038/nbt.2957. View

19.

Chen X, Xu H, Yuan P, Fang F, Huss M, Vega V . Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell. 2008; 133(6):1106-17. DOI: 10.1016/j.cell.2008.04.043. View

20.

Tzouanacou E, Wegener A, Wymeersch F, Wilson V, Nicolas J . Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Dev Cell. 2009; 17(3):365-76. DOI: 10.1016/j.devcel.2009.08.002. View