Developmental Fate and Cellular Maturity Encoded in Human Regulatory DNA Landscapes

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Aug 20

PMID 23953118

Citations 204

Authors

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

Affiliations

Soon will be listed here.

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.

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