Publication Date:
2015-11-26
Description:
DNase I hypersensitive sites (DHSs) provide important information on the presence of transcriptional regulatory elements and the state of chromatin in mammalian cells. Conventional DNase sequencing (DNase-seq) for genome-wide DHSs profiling is limited by the requirement of millions of cells. Here we report an ultrasensitive strategy, called single-cell DNase sequencing (scDNase-seq) for detection of genome-wide DHSs in single cells. We show that DHS patterns at the single-cell level are highly reproducible among individual cells. Among different single cells, highly expressed gene promoters and enhancers associated with multiple active histone modifications display constitutive DHS whereas chromatin regions with fewer histone modifications exhibit high variation of DHS. Furthermore, the single-cell DHSs predict enhancers that regulate cell-specific gene expression programs and the cell-to-cell variations of DHS are predictive of gene expression. Finally, we apply scDNase-seq to pools of tumour cells and pools of normal cells, dissected from formalin-fixed paraffin-embedded tissue slides from patients with thyroid cancer, and detect thousands of tumour-specific DHSs. Many of these DHSs are associated with promoters and enhancers critically involved in cancer development. Analysis of the DHS sequences uncovers one mutation (chr18: 52417839G〉C) in the tumour cells of a patient with follicular thyroid carcinoma, which affects the binding of the tumour suppressor protein p53 and correlates with decreased expression of its target gene TXNL1. In conclusion, scDNase-seq can reliably detect DHSs in single cells, greatly extending the range of applications of DHS analysis both for basic and for translational research, and may provide critical information for personalized medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697938/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697938/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jin, Wenfei -- Tang, Qingsong -- Wan, Mimi -- Cui, Kairong -- Zhang, Yi -- Ren, Gang -- Ni, Bing -- Sklar, Jeffrey -- Przytycka, Teresa M -- Childs, Richard -- Levens, David -- Zhao, Keji -- Z01 HL005801-05/Intramural NIH HHS/ -- England -- Nature. 2015 Dec 3;528(7580):142-6. doi: 10.1038/nature15740.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Systems Biology Center, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Institute of Immunology, Third Military Medical University of the People's Liberation Army, Chongqing 400038, China. ; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China. ; Computational Biology Branch, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605532" target="_blank"〉PubMed〈/a〉
Keywords:
Adenocarcinoma, Follicular/genetics/pathology
;
Animals
;
Chromatin/*genetics/*metabolism
;
Deoxyribonuclease I/*metabolism
;
Enhancer Elements, Genetic/genetics
;
*Formaldehyde
;
Gene Expression Profiling
;
Genome/*genetics
;
Histones/metabolism
;
Humans
;
Mice
;
Mutation/genetics
;
NIH 3T3 Cells
;
*Paraffin Embedding
;
Promoter Regions, Genetic/genetics
;
Reproducibility of Results
;
Single-Cell Analysis/*methods
;
Thioredoxins/genetics
;
Thyroid Neoplasms/genetics/pathology
;
*Tissue Fixation
;
Tumor Suppressor Protein p53/metabolism
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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