title: Local Genome Topology Can Exhibit an Incompletely Rewired 3D-Folding State during Somatic Cell Reprogramming.
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.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Beagan
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gilgenast
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jesi
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Plona
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Heidi K
authors.initials: HK
authors.lastname: Norton
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Gui
authors.initials: G
authors.lastname: Hu
authors.affiliation: Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Shields
authors.affiliation: Department of Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Lyu
authors.affiliation: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA.
authors.forename: Effie
authors.initials: E
authors.lastname: Apostolou
authors.affiliation: Massachusetts General Hospital Cancer Center and Center for Regenerative Medicine, Boston, MA 02114, USA.
authors.forename: Konrad
authors.initials: K
authors.lastname: Hochedlinger
authors.affiliation: Department of Biology, Emory University, Atlanta, GA 30322, USA.
authors.forename: Victor G
authors.initials: VG
authors.lastname: Corces
authors.affiliation: Howard Hughes Medical Institute, Program in Systems Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Job
authors.initials: J
authors.lastname: Dekker
authors.affiliation: 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.
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Phillips-Cremins
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D019070:Cell Lineage / Q000235:genetics; D065150:Cellular Reprogramming / Q000235:genetics*; D002843:Chromatin / Q000737:chemistry; D002999:Clone Cells; D004742:Enhancer Elements, Genetic / Q000235:genetics; D016678:Genome; D057026:Induced Pluripotent Stem Cells / Q000166:cytology; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: D000076246:CCCTC-Binding Factor; D002843:Chromatin; C000619698:Ctcf protein, mouse; D012097:Repressor Proteins