Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops
- Universidade de Lisboa, Portugal
- Universidade Nova de Lisboa, Portugal
Abstract
DNA oxidation by ten-eleven translocation (TET) family enzymes is essential for epigenetic reprogramming. The conversion of 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC) initiates developmental and cell-type-specific transcriptional programs through mechanisms that include changes in the chromatin structure. Here, we show that the presence of 5hmC in the transcribed gene promotes the annealing of the nascent RNA to the template DNA strand, leading to the formation of an R-loop. Depletion of TET enzymes reduced global R-loops in absence of gene expression changes, whereas CRISPR-mediated tethering of TET to an active gene promoted the formation of R-loops. The genome-wide distribution of 5hmC and R-loops show a positive correlation in mouse and human stem cells and overlap in half of all active genes. Moreover, R-loop resolution leads to differential expression of a subset of genes that are involved in crucial events during stem cell proliferation. Altogether, our data reveal that epigenetic reprogramming via TET activity promotes co-transcriptional R-loop formation, disclosing new mechanisms of gene expression regulation.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Madalena R de Almeida
Sérgio Fernandes de Almeida
Funding
Fundação para a Ciência e Tecnologia, Portugal (PTDC/BIA-MOL/30438/2017)
- Sérgio Fernandes de Almeida
Fundação para a Ciência e Tecnologia, Portugal (PTDC/MED-OUT/4301/2020)
- Sérgio Fernandes de Almeida
EU Horizon 2020 Research and Innovation Programme (RiboMed 857119)
- Sérgio Fernandes de Almeida
Fundação para a Ciência e Tecnologia, Portugal (PD/BD/128292/2017)
- João C Sabino
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Sabino 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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Epigenetic reprogramming by TET enzymes impacts co-transcriptional R-loops
eLife 11:e69476.
https://doi.org/10.7554/eLife.69476
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