Biology subjects

Dean, W.

Publications and source records attributed to Dean, W..

3 recordsLinked to original sources

bioRxiv2018

Genome-scale oscillations in DNA methylation during exit from pluripotency

Pluripotency is accompanied by the erasure of parental epigenetic memory with naive pluripotent cells exhibiting global DNA hypomethylation both in vitro and in vivo. Exit from pluripotency and priming for differentiation into somatic lineages is associated with genome-wide de novo DNA methylation. We show that during this phase, coexpression of enzymes required for DNA methylation turnover, DNMT3s and TETs, promotes cell-to-cell variability in this epigenetic mark. Using a combination of single-cell sequencing and quantitative biophysical modelling, we show that this variability is associated with coherent, genome-scale, oscillations in DNA methylation with an amplitude dependent on CpG density. Analysis of parallel single-cell transcriptional and epigenetic profiling provides evidence for oscillatory dynamics both in vitro and in vivo. These observations provide fresh insights into the emergence of epigenetic heterogeneity during early embryo development, indicating that dynamic changes in DNA methylation might influence early cell fate decisions.\n\nHighlightsO_LICo-expression of DNMT3s and TETs drive genome-scale oscillations of DNA methylation\nC_LIO_LIOscillation amplitude is greatest at a CpG density characteristic of enhancers\nC_LIO_LICell synchronisation reveals oscillation period and link with primary transcripts\nC_LIO_LIMultiomic single-cell profiling provides evidence for oscillatory dynamics in vivo\nC_LI

genomics↗

bioRxiv2017

5-Formylcytosine controls nucleosome positioning through covalent histone-DNA interaction

Nucleosomes are the basic unit of chromatin that ensure genome integrity and control access to the genetic information. The organization of nucleosomes is influenced by the underlying DNA sequence itself, transcription factors or other transcriptional machinery associated proteins and chromatin remodeling complexes (1-4). Herein, we show that the naturally occurring DNA modification, 5-formylcytosine (5fC) contributes to the positioning of nucleosomes. We show that the ability of 5fC to position nucleosomes in vitro is associated with the formation of covalent interactions between histone residues and 5fC in the form of Schiff bases. We demonstrate that similar interactions can occur in a cellular environment and define their specific genomic loci in mouse embryonic stem cells. Collectively, our findings identify 5fC as a determinant of nucleosomal organization in which 5fC plays a role in establishing distinct regulatory regions that are linked to gene expression Our study provides a previously unknown molecular mechanism, involving the formation of reversible-covalent bonds between chromatin and DNA that supports a molecular linkage between DNA sequence, DNA base modification and chromatin structure.

genomics↗

bioRxiv2017

A non-catalytic role of TET3 promotes open chromatin and enhances global transcription

The methylcytosine dioxygenase Tet3 is highly expressed as a specific isoform in oocytes and zygotes but essentially absent from later stages of mouse preimplantation development. Here, we show that Tet3 expression promotes transdifferentiation of embryonic stem cells to trophoblast-like stem cells. By genome-wide analyses we demonstrate that TET3 associates with and co-occupies chromatin with RNA Polymerase II. Tet3 expression induces a global increase of transcription and total RNA levels, and its presence further enhances chromatin accessibility in regions open for transcription. This novel function of TET3 is not specific to the oocyte isoform, independent of its catalytic activity, the CXXC domain, or its interaction with OGT, and is localised in its highly conserved exon 4. We propose a more general role for TET3 promoting open chromatin and enhancing global transcription during changes of cellular identity, separate from its catalytic function.

developmental biology↗