Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency

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,...

Full description

Saved in:
Bibliographic Details
Published in:Cell 2015-07, Vol.162 (2), p.412-424
Main Authors: Cacchiarelli, Davide, Trapnell, Cole, Ziller, Michael J., Soumillon, Magali, Cesana, Marcella, Karnik, Rahul, Donaghey, Julie, Smith, Zachary D., Ratanasirintrawoot, Sutheera, Zhang, Xiaolan, Ho Sui, Shannan J., Wu, Zhaoting, Akopian, Veronika, Gifford, Casey A., Doench, John, Rinn, John L., Daley, George Q., Meissner, Alexander, Lander, Eric S., Mikkelsen, Tarjei S.
Format: Article
Language:English
Subjects:
Cellular Reprogramming
Chromatin - metabolism
Chromatin Assembly and Disassembly
Epigenesis, Genetic
Gene Expression Profiling
Histone Demethylases - metabolism
Humans
Induced Pluripotent Stem Cells - cytology
Induced Pluripotent Stem Cells - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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. [Display omitted] [Display omitted] •Immortalized secondary cells enable dissection of human cellular reprogramming•Reprogramming cells show transient re-activation of developmental genes•Transient chromatin remodeling also facilitates direct lineage conversion•Inhibition of the lysine-specific histone demethylase LSD1 enhances reprogramming Systematic dissection of early, intermediate, and late stages of the reprogramming process in an engineered system suitable for integrative genomic analysis of human cellular reprogramming reveals waves of gene network activation and pre-implantation-like signatures.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2015.06.016