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Genome Biol. 2016 Jul 5;17(1):150. doi: 10.1186/s13059-016-1011-3.

Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome.

Gravina S1,2, Dong X3, Yu B3,4,5, Vijg J6.

Author information

1
Department of Genetics, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. sgravina@illumina.com.
2
Present address: Illumina Inc, San Diego, CA, 92122, USA. sgravina@illumina.com.
3
Department of Genetics, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.
4
Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
5
Present address: Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.
6
Department of Genetics, Albert Einstein College of Medicine, Michael F. Price Center, 1301 Morris Park Avenue, Bronx, NY, 10461, USA. jan.vijg@einstein.yu.edu.

Abstract

BACKGROUND:

Transmission fidelity of CpG DNA methylation patterns is not foolproof, with error rates from less than 1 to well over 10 % per CpG site, dependent on preservation of the methylated or unmethylated state and the type of sequence. This suggests a fairly high chance of errors. However, the consequences of such errors in terms of cell-to-cell variation have never been demonstrated by experimentally measuring intra-tissue heterogeneity in an adult organism.

RESULTS:

We employ single-cell DNA methylomics to analyze heterogeneity of genome-wide 5-methylcytosine (5mC) patterns within mouse liver. Our results indicate a surprisingly high level of heterogeneity, corresponding to an average epivariation frequency of approximately 3.3 %, with regions containing H3K4me1 being the most variable and promoters and CpG islands the most stable. Our data also indicate that the level of 5mC heterogeneity is dependent on genomic features. We find that non-functional sites such as repeat elements and introns are mostly unstable and potentially functional sites such as gene promoters are mostly stable.

CONCLUSIONS:

By employing a protocol for whole-genome bisulfite sequencing of single cells, we show that the liver epigenome is highly unstable with an epivariation frequency in DNA methylation patterns of at least two orders of magnitude higher than somatic mutation frequencies.

KEYWORDS:

Aging; Epigenetic instability; Epivariations; Single-cell DNA methylomics; Single-cell epigenomics

PMID:
27380908
PMCID:
PMC4934005
DOI:
10.1186/s13059-016-1011-3
[Indexed for MEDLINE]
Free PMC Article

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