Derepression of Polycomb targets during pancreatic organogenesis allows insulin-producing beta-cells to adopt a neural gene activity program.
- Joris van Arensbergen1,
- Javier Garcia-Hurtado1,
- Ignasi Moran1,
- Miguel Maestro1,
- Xiaobo Xu2,
- Mark Van de Casteele2,
- Anouchka Skoudy3,
- Matteo Palassini4,
- Harry Heimberg2 and
- Jorge Ferrer1,5
- 1 Genomic Programming of Beta Cells, IDIBPAS, Barcelona, Spain;
- 2 Diabetes Research Center, Vrije Universiteit Brussel, Brussels;
- 3 Cancer Research Program, Institut Municipal d'Investigació Mèdica, Barcelona, Spain;
- 4 Departament de Física Fonamental, Universitat de Barcelona, Barcelona, Spain
- * Corresponding author; email: jferrer{at}clinic.ub.es
Abstract
The epigenome changes that underlie cellular differentiation in developing organisms are poorly understood. To gain insights into how pancreatic beta-cells are programmed, we profiled key histone methylations and transcripts in embryonic stem cells, multipotent progenitors of the nascent embryonic pancreas, purified beta-cells, and 10 differentiated tissues. We report that despite their endodermal origin, beta-cells show a transcriptional and active chromatin signature that is most similar to ectoderm-derived neural tissues. In contrast, the beta-cell signature of trimethylated H3K27, a mark of Polycomb-mediated repression, clusters with pancreatic progenitors, acinar cells and liver, consistent with the epigenetic transmission of this mark from endoderm progenitors to their differentiated cellular progeny. We also identified two H3K27 methylation events that arise in the beta-cell lineage after the pancreatic progenitor stage. One is a wave of cell-selective de novo H3K27 trimethylation in non-CpG island genes. Another is the selective loss of H3K27me3-repressed chromatin in a core program of neural developmental regulators that enables a convergence of the gene activity state of beta-cells with that of neural cells. These findings reveal a dynamic regulation of Polycomb repression programs that shape the identity of differentiated beta-cells.
Footnotes
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- Received October 10, 2009.
- Accepted March 23, 2010.
- Copyright © 2010, Cold Spring Harbor Laboratory Press
