title: Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency.
abstract: Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here, we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered re-activation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies. PAPERCLIP.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Davide
authors.initials: D
authors.lastname: Cacchiarelli
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Cole
authors.initials: C
authors.lastname: Trapnell
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ziller
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Magali
authors.initials: M
authors.lastname: Soumillon
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Boston Children's Hospital and Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Marcella
authors.initials: M
authors.lastname: Cesana
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Karnik
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Donaghey
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Zachary D
authors.initials: ZD
authors.lastname: Smith
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Boston Children's Hospital and Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Sutheera
authors.initials: S
authors.lastname: Ratanasirintrawoot
authors.affiliation: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Shannan J
authors.initials: SJ
authors.lastname: Ho Sui
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Boston Children's Hospital and Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: Zhaoting
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Veronika
authors.initials: V
authors.lastname: Akopian
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Casey A
authors.initials: CA
authors.lastname: Gifford
authors.affiliation: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: John
authors.initials: J
authors.lastname: Doench
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: John L
authors.initials: JL
authors.lastname: Rinn
authors.affiliation: Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; Boston Children's Hospital and Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Manton Center for Orphan Disease Research, Howard Hughes Medical Institute, Boston, MA 02115, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meissner
authors.affiliation: Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Lander
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Broad Institute, Cambridge, MA 02142, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: tarjei@broadinstitute.org.
authors.forename: Tarjei S
authors.initials: TS
authors.lastname: Mikkelsen
mesh_terms: D065150:Cellular Reprogramming; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D056466:Histone Demethylases / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D002843:Chromatin; D056466:Histone Demethylases; C495195:KDM1A protein, human