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Cell Stem Cell. 2016 May 5;18(5):611-24. doi: 10.1016/j.stem.2016.04.004.

Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming.

Author information

1
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
2
Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Biology, Emory University, Atlanta, GA 30322, USA.
4
Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA.
5
Howard Hughes Medical Institute, Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
6
Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: jcremins@seas.upenn.edu.

Abstract

Pluripotent genomes are folded in a topological hierarchy that reorganizes during differentiation. The extent to which chromatin architecture is reconfigured during somatic cell reprogramming is poorly understood. Here we integrate fine-resolution architecture maps with epigenetic marks and gene expression in embryonic stem cells (ESCs), neural progenitor cells (NPCs), and NPC-derived induced pluripotent stem cells (iPSCs). We find that most pluripotency genes reconnect to target enhancers during reprogramming. Unexpectedly, some NPC interactions around pluripotency genes persist in our iPSC clone. Pluripotency genes engaged in both "fully-reprogrammed" and "persistent-NPC" interactions exhibit over/undershooting of target expression levels in iPSCs. Additionally, we identify a subset of "poorly reprogrammed" interactions that do not reconnect in iPSCs and display only partially recovered, ESC-specific CTCF occupancy. 2i/LIF can abrogate persistent-NPC interactions, recover poorly reprogrammed interactions, reinstate CTCF occupancy, and restore expression levels. Our results demonstrate that iPSC genomes can exhibit imperfectly rewired 3D-folding linked to inaccurately reprogrammed gene expression.

PMID:
27152443
PMCID:
PMC4859942
DOI:
10.1016/j.stem.2016.04.004
[Indexed for MEDLINE]
Free PMC Article

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