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.
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
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Parkinson’s disease (PD) is a multifactorial disease caused by irreversible progressive loss of dopaminergic neurons (DANs). Recent studies have reported the successful conversion of astrocytes into DANs by repressing polypyrimidine tract binding protein 1 (PTBP1), which led to the rescue of motor symptoms in a chemically-induced mouse model of PD. However, follow-up studies have questioned the validity of this astrocyte-to-DAN conversion model. Here, we devised an adenine base editing strategy to downregulate PTBP1 in astrocytes and neurons in a chemically-induced PD mouse model. While PTBP1 downregulation in astrocytes had no effect, PTBP1 downregulation in neurons of the striatum resulted in the expression of the DAN marker tyrosine hydroxylase (TH) in non-dividing neurons, which was associated with an increase in striatal dopamine concentrations and a rescue of forelimb akinesia and spontaneous rotations. Phenotypic analysis using multiplexed iterative immunofluorescence imaging further revealed that most of these TH-positive cells co-expressed the dopaminergic marker DAT and the pan-neuronal marker NEUN, with the majority of these triple-positive cells being classified as mature GABAergic neurons. Additional research is needed to fully elucidate the molecular mechanisms underlying the expression of the observed markers and understand how the formation of these cells contributes to the rescue of spontaneous motor behaviors. Nevertheless, our findings support a model where downregulation of neuronal, but not astrocytic, PTBP1 can mitigate symptoms in PD mice.
