Strong Components of Epigenetic Memory in Cultured Human Fibroblasts Related to Site of Origin and Donor Age

Autor: Josh G. Chenoweth, Anna C. Brandtjen, Yankai Jia, Nikolay A. Ivanov, Ran Tao, John D. Genova, Michelle I. Mighdoll, Joel E. Kleinman, Andrew E. Jaffe, Thomas M. Hyde, Daniel R. Weinberger, Ronald D.G. McKay
Rok vydání: 2015
Předmět:
0301 basic medicine
Cancer Research
Somatic cell
Molecular biology
Cell Lines
medicine.disease_cause
Biochemistry
Epigenesis
Genetic
Transcriptome
Sequencing techniques
Animal Cells
Medicine and Health Sciences
Child
Genetics (clinical)
Cells
Cultured
Connective Tissue Cells
Aged
80 and over
Genetics
Mutation
DNA methylation
Age Factors
RNA sequencing
Genomics
Middle Aged
Chromatin
Nucleic acids
medicine.anatomical_structure
CpG site
Connective Tissue
Child
Preschool
Epigenetics
Biological Cultures
Cellular Types
Anatomy
DNA modification
Transcriptome Analysis
Chromatin modification
Research Article
Chromosome biology
Adult
lcsh:QH426-470
Adolescent
Biology
Research and Analysis Methods
Polymorphism
Single Nucleotide
03 medical and health sciences
Young Adult
Germline mutation
medicine
Humans
Progenitor cell
Fibroblast
Ecology
Evolution
Behavior and Systematics
Aged
Scalp
Infant
Biology and Life Sciences
Computational Biology
Cell Biology
DNA
Fibroblasts
Genome Analysis
lcsh:Genetics
030104 developmental biology
Biological Tissue
Molecular biology techniques
CpG Islands
Gene expression
Cultured Fibroblasts
Head
Zdroj: PLoS Genetics
PLoS Genetics, Vol 12, Iss 2, p e1005819 (2016)
DOI: 10.1101/025288
Popis: Differentiating pluripotent cells from fibroblast progenitors is a potentially transformative tool in personalized medicine. We previously identified relatively greater success culturing dura-derived fibroblasts than scalp-derived fibroblasts from postmortem tissue. We hypothesized that these differences in culture success were related to epigenetic differences between the cultured fibroblasts by sampling location, and therefore generated genome-wide DNA methylation and transcriptome data on 11 intrinsically matched pairs of dural and scalp fibroblasts from donors across the lifespan (infant to 85 years). While these cultured fibroblasts were several generations removed from the primary tissue and morphologically indistinguishable, we found widespread epigenetic differences by sampling location at the single CpG (N = 101,989), region (N = 697), “block” (N = 243), and global spatial scales suggesting a strong epigenetic memory of original fibroblast location. Furthermore, many of these epigenetic differences manifested in the transcriptome, particularly at the region-level. We further identified 7,265 CpGs and 11 regions showing significant epigenetic memory related to the age of the donor, as well as an overall increased epigenetic variability, preferentially in scalp-derived fibroblasts—83% of loci were more variable in scalp, hypothesized to result from cumulative exposure to environmental stimuli in the primary tissue. By integrating publicly available DNA methylation datasets on individual cell populations in blood and brain, we identified significantly increased inter-individual variability in our scalp- and other skin-derived fibroblasts on a similar scale as epigenetic differences between different lineages of blood cells. Lastly, these epigenetic differences did not appear to be driven by somatic mutation—while we identified 64 probable de-novo variants across the 11 subjects, there was no association between mutation burden and age of the donor (p = 0.71). These results depict a strong component of epigenetic memory in cell culture from primary tissue, even after several generations of daughter cells, related to cell state and donor age.
Author Summary Regenerative medicine specialists have been using a type of cell commonly found in the skin called the fibroblast because it is easily obtained from skin samples, grows well in culture, and can be manipulated in the laboratory to de-differentiate into a primordial state known as the induced pluripotent stem cell. These primitive stem cells can then be transformed into mature tissues, such as liver or pancreas cells. Here we show that fibroblasts, coming from different locations in the same individual, vary significantly in epigenetic marks called DNA methylation, which are involved in the regulation of gene expression. In addition to location-specific patterns of DNA methylation, we also find that fibroblasts from different anatomical locations respond differently in epigenetic patterns related to aging. As the field of regenerative medicine advances, our study demonstrates that deciding upon the source of fibroblasts from an individual to generate new tissues and organs may be an important consideration.
Databáze: OpenAIRE
Externí odkaz: