Single-cell chromatin accessibility reveals principles of regulatory variation

被引:1417
作者
Buenostro, Jason D. [1 ,2 ,3 ]
Wu, Beijing [1 ]
Litzenburger, Ulrike M. [2 ,3 ]
Ruff, Dave [4 ]
Gonzales, Michael L. [4 ]
Snyder, Michael P. [1 ]
Chang, Howard Y. [2 ,3 ]
Greenleaf, William J. [1 ,5 ]
机构
[1] Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA
[2] Stanford Univ, Sch Med, Program Epithelial Biol, Stanford, CA 94305 USA
[3] Stanford Univ, Sch Med, Howard Hughes Med Inst, Stanford, CA 94305 USA
[4] Fluidigm Corp, San Francisco, CA 94080 USA
[5] Stanford Univ, Dept Appl Phys, Stanford, CA 94025 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
RNA-SEQ; DYNAMICS; HETEROGENEITY;
D O I
10.1038/nature14590
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Cell-to-cell variation is a universal feature of life that affects a wide range of biological phenomena, from developmental plasticity(1,2) to tumour heterogeneity(3). Although recent advances have improved our ability to document cellular phenotypic variation(4-8), the fundamental mechanisms that generate variability from identical DNA sequences remain elusive. Here we reveal the landscape and principles of mammalian DNA regulatory variation by developing a robust method for mapping the accessible genome of individual cells by assay for transposase-accessible chromatin using sequencing (ATAC-seq)(9) integrated into a programmable microfluidics platform. Single-cell ATAC-seq (scATAC-seq) maps from hundreds of single cells in aggregate closely resemble accessibility profiles from tens of millions of cells and provide insights into cell-to-cell variation. Accessibility variance is systematically associated with specific trans-factors and cis-elements, and we discover combinations of trans-factors associated with either induction or suppression of cell-to-cell variability. We further identify sets of trans-factors associated with cell-type-specific accessibility variance across eight cell types. Targeted perturbations of cell cycle or transcription factor signalling evoke stimulus-specific changes in this observed variability. The pattern of accessibility variation in cis across the genome recapitulates chromosome compartments(10) de novo, linking single-cell accessibility variation to three-dimensional genome organization. Single-cell analysis of DNA accessibility provides new insight into cellular variation of the 'regulome'.
引用
收藏
页码:486 / U264
页数:15
相关论文
共 28 条
[1]   Rapid, low-input, low-bias construction of shotgun fragment libraries by high-density in vitro transposition [J].
Adey, Andrew ;
Morrison, Hilary G. ;
Asan ;
Xun, Xu ;
Kitzman, Jacob O. ;
Turner, Emily H. ;
Stackhouse, Bethany ;
MacKenzie, Alexandra P. ;
Caruccio, Nicholas C. ;
Zhang, Xiuqing ;
Shendure, Jay .
GENOME BIOLOGY, 2010, 11 (12)
[2]   Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum [J].
Bendall, Sean C. ;
Simonds, Erin F. ;
Qiu, Peng ;
Amir, El-ad D. ;
Krutzik, Peter O. ;
Finck, Rachel ;
Bruggner, Robert V. ;
Melamed, Rachel ;
Trejo, Angelica ;
Ornatsky, Olga I. ;
Balderas, Robert S. ;
Plevritis, Sylvia K. ;
Sachs, Karen ;
Pe'er, Dana ;
Tanner, Scott D. ;
Nolan, Garry P. .
SCIENCE, 2011, 332 (6030) :687-696
[3]  
Buenrostro JD, 2013, NAT METHODS, V10, P1213, DOI [10.1038/NMETH.2688, 10.1038/nmeth.2688]
[4]   Frequency-modulated nuclear localization bursts coordinate gene regulation [J].
Cai, Long ;
Dalal, Chiraj K. ;
Elowitz, Michael B. .
NATURE, 2008, 455 (7212) :485-U16
[5]   Transcriptome-wide noise controls lineage choice in mammalian progenitor cells [J].
Chang, Hannah H. ;
Hemberg, Martin ;
Barahona, Mauricio ;
Ingber, Donald E. ;
Huang, Sui .
NATURE, 2008, 453 (7194) :544-U10
[6]   An integrated encyclopedia of DNA elements in the human genome [J].
Dunham, Ian ;
Kundaje, Anshul ;
Aldred, Shelley F. ;
Collins, Patrick J. ;
Davis, CarrieA. ;
Doyle, Francis ;
Epstein, Charles B. ;
Frietze, Seth ;
Harrow, Jennifer ;
Kaul, Rajinder ;
Khatun, Jainab ;
Lajoie, Bryan R. ;
Landt, Stephen G. ;
Lee, Bum-Kyu ;
Pauli, Florencia ;
Rosenbloom, Kate R. ;
Sabo, Peter ;
Safi, Alexias ;
Sanyal, Amartya ;
Shoresh, Noam ;
Simon, Jeremy M. ;
Song, Lingyun ;
Trinklein, Nathan D. ;
Altshuler, Robert C. ;
Birney, Ewan ;
Brown, James B. ;
Cheng, Chao ;
Djebali, Sarah ;
Dong, Xianjun ;
Dunham, Ian ;
Ernst, Jason ;
Furey, Terrence S. ;
Gerstein, Mark ;
Giardine, Belinda ;
Greven, Melissa ;
Hardison, Ross C. ;
Harris, Robert S. ;
Herrero, Javier ;
Hoffman, Michael M. ;
Iyer, Sowmya ;
Kellis, Manolis ;
Khatun, Jainab ;
Kheradpour, Pouya ;
Kundaje, Anshul ;
Lassmann, Timo ;
Li, Qunhua ;
Lin, Xinying ;
Marinov, Georgi K. ;
Merkel, Angelika ;
Mortazavi, Ali .
NATURE, 2012, 489 (7414) :57-74
[7]   Mapping and analysis of chromatin state dynamics in nine human cell types [J].
Ernst, Jason ;
Kheradpour, Pouya ;
Mikkelsen, Tarjei S. ;
Shoresh, Noam ;
Ward, Lucas D. ;
Epstein, Charles B. ;
Zhang, Xiaolan ;
Wang, Li ;
Issner, Robbyn ;
Coyne, Michael ;
Ku, Manching ;
Durham, Timothy ;
Kellis, Manolis ;
Bernstein, Bradley E. .
NATURE, 2011, 473 (7345) :43-U52
[8]   Architecture of the human regulatory network derived from ENCODE data [J].
Gerstein, Mark B. ;
Kundaje, Anshul ;
Hariharan, Manoj ;
Landt, Stephen G. ;
Yan, Koon-Kiu ;
Cheng, Chao ;
Mu, Xinmeng Jasmine ;
Khurana, Ekta ;
Rozowsky, Joel ;
Alexander, Roger ;
Min, Renqiang ;
Alves, Pedro ;
Abyzov, Alexej ;
Addleman, Nick ;
Bhardwaj, Nitin ;
Boyle, Alan P. ;
Cayting, Philip ;
Charos, Alexandra ;
Chen, David Z. ;
Cheng, Yong ;
Clarke, Declan ;
Eastman, Catharine ;
Euskirchen, Ghia ;
Frietze, Seth ;
Fu, Yao ;
Gertz, Jason ;
Grubert, Fabian ;
Harmanci, Arif ;
Jain, Preti ;
Kasowski, Maya ;
Lacroute, Phil ;
Leng, Jing ;
Lian, Jin ;
Monahan, Hannah ;
O'Geen, Henriette ;
Ouyang, Zhengqing ;
Partridge, E. Christopher ;
Patacsil, Dorrelyn ;
Pauli, Florencia ;
Raha, Debasish ;
Ramirez, Lucia ;
Reddy, Timothy E. ;
Reed, Brian ;
Shi, Minyi ;
Slifer, Teri ;
Wang, Jing ;
Wu, Linfeng ;
Yang, Xinqiong ;
Yip, Kevin Y. ;
Zilberman-Schapira, Gili .
NATURE, 2012, 489 (7414) :91-100
[9]   Predictive Polymer Modeling Reveals Coupled Fluctuations in Chromosome Conformation and Transcription [J].
Giorgetti, Luca ;
Galupa, Rafael ;
Nora, Elphege P. ;
Piolot, Tristan ;
Lam, France ;
Dekker, Job ;
Tiana, Guido ;
Heard, Edith .
CELL, 2014, 157 (04) :950-963
[10]   Tn5 in vitro transposition [J].
Goryshin, IY ;
Reznikoff, WS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (13) :7367-7374