Investigating stem cells in human colon by using methylation patterns
- *Department of Pathology, University of Southern California School of Medicine, Los Angeles, CA 90033; and ‡Departments of Biological Sciences, Mathematics, and Preventive Medicine, University of Southern California, Los Angeles, CA 90089
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Edited by Bert Vogelstein, Johns Hopkins Oncology Center, Baltimore, MD, and approved July 12, 2001 (received for review May 7, 2001)
Abstract
The stem cells that maintain human colon crypts are poorly characterized. To better determine stem cell numbers and how they divide, epigenetic patterns were used as cell fate markers. Methylation exhibits somatic inheritance and random changes that potentially record lifelong stem cell division histories as binary strings or tags in adjacent CpG sites. Methylation tag contents of individual crypts were sampled with bisulfite sequencing at three presumably neutral loci. Methylation increased with aging but varied between crypts and was mosaic within single crypts. Some crypts appeared to be quasi-clonal as they contained more unique tags than expected if crypts were maintained by single immortal stem cells. The complex epigenetic patterns were more consistent with a crypt niche model wherein multiple stem cells were present and replaced through periodic symmetric divisions. Methylation tags provide evidence that normal human crypts are long-lived, accumulate random methylation errors, and contain multiple stem cells that go through “bottlenecks” during life.
Footnotes
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↵ † Present address: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya 464-8681, Japan.
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↵ § To whom reprint requests should be addressed at: University of Southern California School of Medicine, 1200 North State Street, Box 736, Los Angeles, CA 90033. E-mail: dshibata{at}hsc.usc.edu.
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This paper was submitted directly (Track II) to the PNAS office.
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See commentary on page 10519.
- Abbreviations:
- MYOD1,
- myogenic factor 3;
- CSX,
- cardiac-specific homeobox;
- BGN,
- biglycan
- Copyright © 2001, The National Academy of Sciences
