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Epitranscriptomic regulation of embryo development: function of RNA modifications during the maternal to zygotic transition of vertebrate embryos

Primary Supervisor: Dr Matthias Soller, School of Biosciences

Secondary Supervisor: Professor Ferenc Mueller, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences

PhD project title: Epitranscriptomic regulation of embryo development: function of RNA modifications during the maternal to zygotic transition of vertebrate embryos

University of Registration: University of Birmingham

Project outline:

A lot is know about how DNA modifications influence the reading of the codes embedded in the DNA sequence. It has recently become apparent that RNAs also carry many such modifications and they influence how information in the RNA is processed and read by proteins (Haussmann et al., 2016). Most mRNAs contain modified nucleotides in mRNA, but we know very little about their function (Dezi et al, 2016, Roignant and Soller, 2017) and biology and biochemistry of RNA modifications represent a fast expanding discipline.

Global and dynamic reprogramming of the epigenome (DNA methylation and chromatin) in early embryos is essential to prepare the genome of the terminally differentiated egg to transition into pluripotency and subsequently to embryo differentiation (Reik et al., 2007). This reprogramming coincides with the most dramatic transition of gene expression programmes during ontogeny – the maternal to zygotic transition (MZT), which involves regulated degradation of maternal RNAs and dramatic activation of large number of genes of the embryo. Maternal mRNAs, which are deposited by the mother into the oocytes before fertilization are particularly enriched in modified nucleotides in RNAs (epitranscriptome). This observation suggests a fundamental role for RNA modifications in the switch from the maternal to the zygotic (embryo-produced) transcriptome.

The MZT in zebrafish represents an excellent in vivo model for studying the establishment of pluripotency in embryos. In particular, histone and DNA modification marks have instructive roles to establish the developmental gene expression programme, but whether methyl marks in mRNA are instructed by histone modification and how exactly they contribute to early embryonic development has not been addressed.

Objectives: Here we plan to study how the transition and regulation of epigenetic signals (histone marks and DNA methylation) from parents to the embryo impacts on mRNA methylation. We will capitalize on high-resolution histone modification maps available in the lab (Haberle et al., 2014) and compare them with the presence of methylmarks in mRNA, occupancy of the methylosome and interpretation of epimarks by modification reader proteins. This genome wide data will then be analysed to establish the correlations between the epitranscriptome and epigenetic features as well as transcriptional responses of the developing embryo. Predictions made from this genome-wide analysis will then be validated by zebrafish transgenesis. In the long term, this groundwork will allow us to address the role of the epitranscriptome in the communication between genomes and epigenetic mechanisms in transgenerational inheritance.

References:

  1. Haussmann, I.U., Bodi, Z., Sanchez-Moran, E., Mongan, N., Archer, N., Fray, R., and Soller, M. (2016) m6A potentiates Sxl alternative pre-mRNA splicing for robust Drosophila sex determination. Nature 540:301-304.
  2. Dezi, V., Ivanov, C., Haussmann, I. U. and Soller, M. (2016) mRNA modifications and their role in development and disease. Biochem. Soc. Trans. 44: 1385-93.
  3. Haberle, V, Li, N., Hadzhiev, Y., Plessy, C., Previti, C., Nepal, C., Gehrig, J., Dong, X., Akalin, A., Suzuki, A-M., van IJcken, W., Armant, O., Ferg, M., Strähle, U., Carninci, P., Müller F.*, Lenhard B. Two independent transcription initiation codes overlap on vertebrate core promoters. Nature, 507(7492):381-5, , *co-corresponding author
  4. Reik, W. Nature 447, 425-432(2007).
  5. Roignant, JY and Soller, M. (2017). m6A in mRNA: An ancient mechanism for fine-tuning gene expression. Opinion Article. Trends in Genetics 33: 380-90.

BBSRC Strategic Research Priority: Understanding the Rules of Life: Stem Cells

Techniques that will be undertaken during the project:

  • Chromatin and RNA modification-specific immounoprecipitation

  • Illumina sequencing

  • mRNA modification analysis

  • Zebrafish CRISPR/CAS9 mutagenesis and transgenesis

  • Fluorescence microscopy

  • Sequence data analysis, and statistical analysis of genomics data, bioinformatics and programming (R).

Contact: Dr Matthias Soller, University of Birmingham