Biology subjects

Drage, D.

Publications and source records attributed to Drage, D..

4 recordsLinked to original sources

bioRxiv2023

Maternal SMARCA5 is required for major ZGA in mouse embryos

Zygotic genome activation (ZGA) in mice takes place in two waves, a minor wave in the one-cell embryo, and a major wave at the two-cell stage, both accompanied by global transcriptional and epigenetic reprogramming. However, the orchestration of these reprogramming events by maternal factors deposited in the oocyte is not yet entirely understood. We and others have recently shown that epigenetic modifiers such as SMARCA5 (the main ATPase in ISWI complexes) can initiate the ZGA transcriptional programme in vitro. So far, the role of SMARCA5 in ZGA in vivo has not been addressed, as constitutive knock-out mice lacking SMARCA5 are not viable. We have overcome this limitation by using the targeted protein-depletion system Trim Away to degrade SMARCA5 in early zygotes. We further harnessed the power of single cell multi-omics (scNMT-seq) and showed that in the absence of SMARCA5, major ZGA genes fail to be upregulated at the two-cell stage. This is explained by the lower accessibility and disrupted nucleosome positioning at their promoters and distal regulatory regions, compared to wild-type embryos. In contrast, we show that global chromatin accessibility at the two-cell stage is higher in SMARCA5 depleted embryos compared to control embryos, and this is accompanied by other global structural changes involving heterochromatic regions. Our results show that SMARCA5 has a global regulatory role at the two-cell stage, which includes the control of ZGA gene promoters and distal regulatory regions.

developmental biology↗

bioRxiv2022

Decoding gene regulation in the mouse embryo using single-cell multi-omics

Following gastrulation, the three primary germ layers develop into the major organs in a process known as organogenesis. Single-cell RNA sequencing has enabled the profiling of the gene expression dynamics of these cell fate decisions, yet a comprehensive map of the interplay between transcription factors and cis-regulatory elements is lacking, as are the underlying gene regulatory networks. Here we generate a multi-omics atlas of mouse early organogenesis by simultaneously profiling gene expression and chromatin accessibility from tens of thousands of single cells. We develop a computational method to leverage the multimodal readouts to predict transcription factor binding events in cis-regulatory elements, which we then use to infer gene regulatory networks that underpin lineage commitment events. Finally, we show that these models can be used to generate in silico predictions of the effect of transcription factor perturbations. We validate this experimentally by showing that Brachyury is essential for the differentiation of neuromesodermal progenitors to somitic mesoderm fate by priming cis-regulatory elements. The data set can be interactively explored at https://www.bioinformatics.babraham.ac.uk/shiny/shiny_multiome_organogenesis/

developmental biology↗

bioRxiv2021

Maternal Dppa2 and Dppa4 are dispensable for zygotic genome activation but important for offspring survival

Zygotic Genome Activation (ZGA) represents the initiation of transcription following fertilisation. Despite its importance in shifting developmental control from primarily maternal stores in the oocyte to the embryo proper, we know little of the molecular events that initiate ZGA in vivo. Recent in vitro studies in mouse embryonic stem cells (ESCs) have revealed Developmental Pluripotency Associated 2 and 4 (Dppa2/4) as key regulators of ZGA-associated transcription. However, their roles in initiating ZGA in vivo remain unexplored. We reveal Dppa2/4 proteins are present in the nucleus at all stages of preimplantation development and associate with mitotic chromatin. We generated single and double maternal knockout mouse models to deplete maternal stores of Dppa2/4. Importantly, while fertile, Dppa2/4 maternal knockout mice had reduced litter sizes, indicating decreased offspring survival. Immunofluorescence and transcriptome analyses of 2-cell embryos revealed while ZGA took place there were subtle defects in embryos lacking maternal Dppa2/4. Strikingly, heterozygous offspring that inherited the null allele maternally had higher preweaning lethality than those that inherited the null allele paternally. Together our results show that while Dppa2/4 are dispensable for ZGA transcription, maternal stores have an important role in offspring survival, potentially via epigenetic priming of developmental genes.

developmental biology↗

bioRxiv2019

Differential sperm motility mediates the sex ratio drive shaping mouse sex chromosome evolution

SummaryThe search for morphological or physiological differences between X- and Y-bearing mammalian sperm has provoked controversy for decades. Many potential differences have been proposed, but none validated, while accumulating understanding of syncytial sperm development has cast doubt on whether such differences are possible even in principle. We present the first ever mammalian experimental model to trace a direct link from a measurable physiological difference between X- and Y-bearing sperm to the resulting skewed sex ratio. We show that in mice with deletions on chromosome Yq, birth sex ratio distortion is due to a relatively greater motility of X-bearing sperm, and not to any aspect of sperm/egg interaction. Moreover, the morphological distortion caused by Yq deletion is more severe in Y-bearing sperm, providing a potential hydrodynamic basis for the altered motility. This reinforces a growing body of work indicating that sperm haploid selection is an important and underappreciated evolutionary force.

developmental biology↗