Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells

TY - JOUR

T1 - Dynamic chromatin remodeling mediated by polycomb proteins orchestrates pancreatic differentiation of human embryonic stem cells

AU - Xie, Ruiyu

AU - Everett, Logan J

AU - Lim, Hee-Woong

AU - Patel, Nisha A

AU - Schug, Jonathan

AU - Kroon, Evert

AU - Kelly, Olivia G

AU - Wang, Allen

AU - D'Amour, Kevin A

AU - Robins, Allan J

AU - Won, Kyoung-Jae

AU - Kaestner, Klaus H

AU - Sander, Maike

N1 - Copyright © 2013 Elsevier Inc. All rights reserved.

PY - 2013/2/7

Y1 - 2013/2/7

N2 - Embryonic development is characterized by dynamic changes in gene expression, yet the role of chromatin remodeling in these cellular transitions remains elusive. To address this question, we profiled the transcriptome and select chromatin modifications at defined stages during pancreatic endocrine differentiation of human embryonic stem cells. We identify removal of Polycomb group (PcG)-mediated repression on stage-specific genes as a key mechanism for the induction of developmental regulators. Furthermore, we discover that silencing of transitory genes during lineage progression associates with reinstatement of PcG-dependent repression. Significantly, in vivo- but not in vitro-differentiated endocrine cells exhibit close similarity to primary human islets in regard to transcriptome and chromatin structure. We further demonstrate that endocrine cells produced in vitro do not fully eliminate PcG-mediated repression on endocrine-specific genes, probably contributing to their malfunction. These studies reveal dynamic chromatin remodeling during developmental lineage progression and identify possible strategies for improving cell differentiation in culture.

AB - Embryonic development is characterized by dynamic changes in gene expression, yet the role of chromatin remodeling in these cellular transitions remains elusive. To address this question, we profiled the transcriptome and select chromatin modifications at defined stages during pancreatic endocrine differentiation of human embryonic stem cells. We identify removal of Polycomb group (PcG)-mediated repression on stage-specific genes as a key mechanism for the induction of developmental regulators. Furthermore, we discover that silencing of transitory genes during lineage progression associates with reinstatement of PcG-dependent repression. Significantly, in vivo- but not in vitro-differentiated endocrine cells exhibit close similarity to primary human islets in regard to transcriptome and chromatin structure. We further demonstrate that endocrine cells produced in vitro do not fully eliminate PcG-mediated repression on endocrine-specific genes, probably contributing to their malfunction. These studies reveal dynamic chromatin remodeling during developmental lineage progression and identify possible strategies for improving cell differentiation in culture.

KW - Animals

KW - Cell Differentiation/genetics

KW - Chromatin Assembly and Disassembly/genetics

KW - Embryonic Stem Cells/cytology

KW - Endocrine Cells/cytology

KW - Endoderm/cytology

KW - Humans

KW - Mice

KW - Pancreas/cytology

KW - Polycomb-Group Proteins/genetics

U2 - 10.1016/j.stem.2012.11.023

DO - 10.1016/j.stem.2012.11.023

M3 - Journal article

C2 - 23318056

SN - 1934-5909

VL - 12

SP - 224

EP - 237

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 2

ER -