Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells
- The Babraham Institute, United Kingdom
- Universidad Nacional Autónoma de México, Mexico
- King's College London School of Medicine, United Kingdom
Abstract
Long-range cis-regulatory elements such as enhancers coordinate cell-specific transcriptional programmes by engaging in DNA looping interactions with target promoters. Deciphering the interplay between the promoter connectivity and activity of cis-regulatory elements during lineage commitment is crucial for understanding developmental transcriptional control. Here, we use Promoter Capture Hi-C to generate a high-resolution atlas of chromosomal interactions involving ~22,000 gene promoters in human pluripotent and lineage-committed cells, identifying putative target genes for known and predicted enhancer elements. We reveal extensive dynamics of cis-regulatory contacts upon lineage commitment, including the acquisition and loss of promoter interactions. This spatial rewiring occurs preferentially with predicted changes in the activity of cis-regulatory elements, and is associated with changes in target gene expression. Our results provide a global and integrated view of promoter interactome dynamics during lineage commitment of human pluripotent cells.
Data availability
-
Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE76626).
-
Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cellsPublicly available via the Open Science Framework.
-
A unique chromatin signature uncovers early developmental enhancers in humansPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE24447).
Article and author information
Author details
Funding
Wellcome (WT093736)
- Peter J Rugg-Gunn
Biotechnology and Biological Sciences Research Council (BB/J004480/1)
- Paula Freire-Pritchett
- Stefan Schoenfelder
- Csilla Várnai
- Steven W Wingett
- Jonathan Cairns
- Mayra Furlan-Magaril
- Peter J Fraser
- Mikhail Spivakov
Medical Research Council (MR/J003808/1)
- Amanda J Collier
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Job Dekker, University of Massachusetts Medical School, United States
Version history
- Received: September 28, 2016
- Accepted: March 22, 2017
- Accepted Manuscript published: March 23, 2017 (version 1)
- Version of Record published: April 27, 2017 (version 2)
Copyright
© 2017, Freire-Pritchett et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 6,010
- Page views
-
- 1,429
- Downloads
-
- 92
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Global reorganisation of cis-regulatory units upon lineage commitment of human embryonic stem cells
eLife 6:e21926.
https://doi.org/10.7554/eLife.21926
Further reading
-
- Stem Cells and Regenerative Medicine
In vitro culture systems that structurally model human myogenesis and promote PAX7+ myogenic progenitor maturation have not been established. Here we report that human skeletal muscle organoids can be differentiated from induced pluripotent stem cell lines to contain paraxial mesoderm and neuromesodermal progenitors and develop into organized structures reassembling neural plate border and dermomyotome. Culture conditions instigate neural lineage arrest and promote fetal hypaxial myogenesis toward limb axial anatomical identity, with generation of sustainable uncommitted PAX7 myogenic progenitors and fibroadipogenic (PDGFRa+) progenitor populations equivalent to those from the second trimester of human gestation. Single-cell comparison to human fetal and adult myogenic progenitor /satellite cells reveals distinct molecular signatures for non-dividing myogenic progenitors in activated (CD44High/CD98+/MYOD1+) and dormant (PAX7High/FBN1High/SPRY1High) states. Our approach provides a robust 3D in vitro developmental system for investigating muscle tissue morphogenesis and homeostasis.
-
- Developmental Biology
- Stem Cells and Regenerative Medicine
During human forebrain development, neural progenitor cells (NPCs) in the ventricular zone (VZ) undergo asymmetric cell divisions to produce a self-renewed progenitor cell, maintaining the potential to go through additional rounds of cell divisions, and differentiating daughter cells, populating the developing cortex. Previous work in the embryonic rodent brain suggested that the preferential inheritance of the pre-existing (older) centrosome to the self-renewed progenitor cell is required to maintain stem cell properties, ensuring proper neurogenesis. If asymmetric segregation of centrosomes occurs in NPCs of the developing human brain, which depends on unique molecular regulators and species-specific cellular composition, remains unknown. Using a novel, recombination-induced tag exchange-based genetic tool to birthdate and track the segregation of centrosomes over multiple cell divisions in human embryonic stem cell-derived regionalised forebrain organoids, we show the preferential inheritance of the older mother centrosome towards self-renewed NPCs. Aberration of asymmetric segregation of centrosomes by genetic manipulation of the centrosomal, microtubule-associated protein Ninein alters fate decisions of NPCs and their maintenance in the VZ of human cortical organoids. Thus, the data described here use a novel genetic approach to birthdate centrosomes in human cells and identify asymmetric inheritance of centrosomes as a mechanism to maintain self-renewal properties and to ensure proper neurogenesis in human NPCs.
