Developmental fate and cellular maturity encoded in human regulatory DNA landscapes

Andrew B. Stergachis, Shane Neph, Alex Reynolds, Richard Humbert, Brady Miller, Sharon L. Paige, Benjamin Vernot, Jeffrey B. Cheng, Robert E. Thurman, Richard Sandstrom, Eric Haugen, Shelly Heimfeld, Charles E. Murry, Joshua M. Akey, John A. Stamatoyannopoulos

Research output: Contribution to journalArticle

184 Scopus citations

Abstract

Cellular-state information between generations of developing cells may be propagated via regulatory regions. We report consistent patterns of gain and loss of DNase I-hypersensitive sites (DHSs) as cells progress from embryonic stem cells (ESCs) to terminal fates. DHS patterns alone convey rich information about cell fate and lineage relationships distinct from information conveyed by gene expression. Developing cells share a proportion of their DHS landscapes with ESCs; that proportion decreases continuously in each cell type as differentiation progresses, providing a quantitative benchmark of developmental maturity. Developmentally stable DHSs densely encode binding sites for transcription factors involved in autoregulatory feedback circuits. In contrast to normal cells, cancer cells extensively reactivate silenced ESC DHSs and those from developmental programs external to the cell lineage from which the malignancy derives. Our results point to changes in regulatory DNA landscapes as quantitative indicators of cell-fate transitions, lineage relationships, and dysfunction. PaperClip

Original languageEnglish (US)
Pages (from-to)888-903
Number of pages16
JournalCell
Volume154
Issue number4
DOIs
StatePublished - Aug 15 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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    Stergachis, A. B., Neph, S., Reynolds, A., Humbert, R., Miller, B., Paige, S. L., Vernot, B., Cheng, J. B., Thurman, R. E., Sandstrom, R., Haugen, E., Heimfeld, S., Murry, C. E., Akey, J. M., & Stamatoyannopoulos, J. A. (2013). Developmental fate and cellular maturity encoded in human regulatory DNA landscapes. Cell, 154(4), 888-903. https://doi.org/10.1016/j.cell.2013.07.020