Widespread Chromatin Accessibility at Repetitive Elements Links Stem Cells with Human Cancer.
Chromatin regulation is critical for differentiation and disease. However, features linking the chromatin environment of stem cells with disease remain largely unknown. We explored chromatin accessibility in embryonic and multipotent stem cells and unexpectedly identified widespread chromatin accessibility at repetitive elements. Integrating genomic and biochemical approaches, we demonstrate that these sites of increased accessibility are associated with well-positioned nucleosomes marked by distinct histone modifications. Differentiation is accompanied by chromatin remodeling at repetitive elements associated with altered expression of genes in relevant developmental pathways. Remarkably, we found that the chromatin environment of Ewing sarcoma, a mesenchymally derived tumor, is shared with primary mesenchymal stem cells (MSCs). Accessibility at repetitive elements in MSCs offers a permissive environment that is exploited by the critical oncogene responsible for this cancer. Our data demonstrate that stem cells harbor a unique chromatin landscape characterized by accessibility at repetitive elements, a feature associated with differentiation and oncogenesis.
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
Nicholas C
NC
Gomez
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
Austin J
AJ
Hepperla
Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Human Pluripotent Stem Cell Core Facility, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
Raluca
R
Dumitru
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
Jeremy M
JM
Simon
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
Fang
F
Fang
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pediatrics, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: ian_davis@med.unc.edu.
Ian J
IJ
Davis
D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D003851:Deoxyribonucleases / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D009707:Nucleosomes / Q000378:metabolism; D009857:Oncogenes; D011499:Protein Processing, Post-Translational; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics*; D020086:Short Interspersed Nucleotide Elements / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism*; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D009707:Nucleosomes; D003851:Deoxyribonucleases
Ewing sarcoma; cancer; chromatin; chromatin accessibility; differentiation; histone modification; repetitive elements; stem cell