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

• Type of Material: Article
• Authors: Jonathan A. Beagan, University of Pennsylvania; Thomas G. Gilgenast, University of Pennsylvania; Jesi Kim, University of Pennsylvania; Zachary Plona, University of Pennsylvania; Heidi K. Norton, University of Pennsylvania; Gui Hu, University of Pennsylvania; Sarah C. Hsu, University of Pennsylvania; Emily J. Shields, University of Pennsylvania; Xiaowen Lyu, Emory University; Effie Apostolou, Massachusetts General Hospital; Konrad Hochedlinger, Massachusetts General Hospital; Victor Corces, Emory University; Job Dekker, University of Massachusetts; Jennifer E. Phillips-Cremins, University of Pennsylvania
• Language: English
• Date: 2016-05-05
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Elsevier Inc.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.stem.2016.04.004
• Title of Journal or Parent Work: Cell Stem Cell
• Volume: 18
• Issue: 5
• Start Page: 611
• End Page: 624
• Grant/Funding Information: This work was funded by The New York Stem Cell Foundation (J.E.P.C), the Alfred P. Sloan Foundation (J.E.P.C), the NIH Director’s New Innovator Award from the National Institute of Mental Health (1DP2MH11024701; J.E.P.C), 4D Nucleome Common Fund grants (1U01HL12999801 to J.E.P.C; U54DK107980 to J.D.) and an R01 from the National Human Genome Research Institute (R01 HG003143; J.D.).
• Keywords: DIFFERENTIATION; EXPRESSION; INTERACTOME; REORGANIZATION; PLURIPOTENT STEM-CELLS; ORGANIZATION; GENE; MOUSE; Science & Technology; Cell Biology; Cell & Tissue Engineering; Life Sciences & Biomedicine; CHROMATIN ARCHITECTURE; GROUND-STATE
• Research Categories: Biology, Genetics; Biology, Cell

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.