Journal
CELL STEM CELL
Volume 18, Issue 5, Pages 611-624Publisher
CELL PRESS
DOI: 10.1016/j.stem.2016.04.004
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Funding
- New York Stem Cell Foundation
- Alfred P. Sloan Foundation
- NIH Director's New Innovator Award from the National Institute of Mental Health [1DP2MH11024701]
- 4D Nucleome Common Fund [1U01HL12999801, U54DK107980]
- National Human Genome Research Institute [R01 HG003143]
- Direct For Mathematical & Physical Scien
- Division Of Mathematical Sciences [1562665] Funding Source: National Science Foundation
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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.
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