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
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Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE76626).
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Global rewiring of cis-regulatory units upon lineage commitment of human embryonic stem cellsPublicly available via the Open Science Framework.
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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.
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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
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While accumulated publications support the existence of neurogenesis in the adult human hippocampus, the homeostasis and developmental potentials of neural stem cells (NSCs) under different contexts remain unclear. Based on our generated single-nucleus atlas of the human hippocampus across neonatal, adult, aging, and injury, we dissected the molecular heterogeneity and transcriptional dynamics of human hippocampal NSCs under different contexts. We further identified new specific neurogenic lineage markers that overcome the lack of specificity found in some well-known markers. Based on developmental trajectory and molecular signatures, we found that a subset of NSCs exhibit quiescent properties after birth, and most NSCs become deep quiescence during aging. Furthermore, certain deep quiescent NSCs are reactivated following stroke injury. Together, our findings provide valuable insights into the development, aging, and reactivation of the human hippocampal NSCs, and help to explain why adult hippocampal neurogenesis is infrequently observed in humans.
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We developed a 96-well plate assay which allows fast, reproducible, and high-throughput generation of 3D cardiac rings around a deformable optically transparent hydrogel (polyethylene glycol [PEG]) pillar of known stiffness. Human induced pluripotent stem cell-derived cardiomyocytes, mixed with normal human adult dermal fibroblasts in an optimized 3:1 ratio, self-organized to form ring-shaped cardiac constructs. Immunostaining showed that the fibroblasts form a basal layer in contact with the glass, stabilizing the muscular fiber above. Tissues started contracting around the pillar at D1 and their fractional shortening increased until D7, reaching a plateau at 25±1%, that was maintained up to 14 days. The average stress, calculated from the compaction of the central pillar during contractions, was 1.4±0.4 mN/mm2. The cardiac constructs recapitulated expected inotropic responses to calcium and various drugs (isoproterenol, verapamil) as well as the arrhythmogenic effects of dofetilide. This versatile high-throughput assay allows multiple in situ mechanical and structural readouts.
