Primary Supervisor: Dr Matthias Soller, School of Biosciences
Secondary supervisor: Dr Ferenc Mueller, Institute of Cancer and Genomic Sciences, College of Medial and Dental Sciences
PhD project title: Epitranscriptomic mechanisms in the maternal to zygotic transition of vertebrate embryos
University of Registration: University of Birmingham
Most mRNAs contain modified nucleotides in mRNA, but we know very little about their function (Haussmann et al, 2016, Dezi et al, 2016, Roignant and Soller, 2017). Maternal mRNA in oocytes is particularly enriched in modified nucleotides suggesting a fundamental role in the switch from the maternal to the zygotic transcriptome.
Global and dynamic reprogramming of the epigenome (DNA methylation and chromatin) in early embryos is essential to prepare the genome for pluripotency and 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 (reviewed in Vastenhouw et al., 2012).
Recent developments in understanding the genetic and epigenetic mechanisms of transcriptional regulation during zygotic genome activation brings the MZT in zebrafish and other vertebrate models into centre of focus as it represents an in vivo model for establishment of pluripotency in embryos (Leichsenring et al., 2013). The Muller laboratory has been studying the interplay between transcription regulation and epigenetic regulation during embryo development. Using the zebrafish embryo we and others have established that histone modification marks associated with gene regulatory elements such as enhancers and promoters of protein coding genes are present on the regulatory elements well before zygotic genome gets activated (Lindeman et al., 2012, Vastenhouw et al., 2010, Haberle et al., 2014). This observation suggests potential instructive role for histone and DNA modification marks in establishing the developmental gene expression programme. The presence of such histone marks in the sperm (Hammoud et al., 2009) raises the question whether these epigenetic signals represent an inherited set of instructions for development. Likewise, whether methylmarks 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 address 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 form this genome-wide analysis will then be validated by zebrafish transgenesis (Anderson et al., 2013, Gehrig et al., 2009). 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.
- Andersson, R., Gebhard, C., Miguel, I., Hoof, I., Zhao, X., Schmidl, C., Valen, E., Li, K., Schwarzfischer, L., Glatz, D., Raithel, J., Chen, Y., Lilje, B., Rapin, N., Otzen Bagger, F., Jørgensen, M., Boyd, M., Bornholdt Lange, J., Baillie, K., Mungall, C., Lassman, T., Kawaji, H., Lennartsson, A., Daub, C., Hume, D., Heutink, P., Krogh, A., Hayashizaki, Y., Müller, F., Forrest, F., Carninci, P., Rehli, M., Sandelin A. Systematic in-vivo characterization of active enhancers across the human body Nature
- 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.
- 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
- Hammoud, S. et al. Nature 460, 473-478(2009)
- 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.
- Leichsenring, Et al., Science. 2013 Aug 30;341(6149):1005-9.
- Lindeman, I.S. Andersen, A.H. Reiner, N. Li, Håvard, Aanes, O. Østrup, C. Winata, S. Mathavan, F. Müller, P. Aleström, and P. Collas (2011) Pre-patterning of Developmental Gene Expression by Modified Histones before Zygotic Genome Activation. Dev Cell, 21(6):993-1004
- Nepal C, Hadzhiev, Y., Previti, C., Haberle V., Li, N., Takahashi, H., Suzuki, A-M. S., Sheng, Y., Abdelhamid, R.A., Anand, S., Gehrig, J., Akalin, A., Kockx, C.E.M. van der Sloot, A.A.J., van IJcken, W.F.J., Armant, O., Rastegar, S., Watson, C., Strähle, U., Stupka, E., Carninci, P., Lenhard B., and Müller F. (2013) Dynamic regulation of the transcription initiation landscape at single nucleotide resolution during vertebrate embryogenesis. Genome Research, 2013 Sep 3.
- Reik, W. Nature 447, 425-432(2007).
- 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.
- Vastenhouw, N. et al. Nature 464, 922-926 (2010)
- Vastenhouw, N. L. et al. Curr Opin Cell Biol 24, 374-386(2012)
BBSRC Strategic Research Priority: Understanding the Rules of Life: Stem Cells
Techniques that will be undertaken during the project:
Chromatin and RNA modification-specific immounoprecitation, Illumina sequencing, mRNA modification analysis, zebrafish CRISPR/CAS9 mutagenesis and transgenesis, fluorescence microscopy, sequence data analysis, and statistical analysis
Contact: Dr Matthias Soller, University of Birmingham