Investigating the role for epigenetic modifier MLL2 in placental development

Supervised by: Courtney Hanna (cwh36@cam.ac.uk) & Miguel Constancia (jmasmc2@cam.ac.uk) 

Project Title

Investigating the role for epigenetic modifier MLL2 in placental development

Project description

The placenta forms the maternal-foetal interface in pregnancy, controlling nutrient and waste exchange, hormone production and immunotolerance between mother and foetus. Impaired placental function has been widely linked to poor pregnancy outcomes. However, we currently have little understanding of the early regulators of placental development that lead to a functional placenta and healthy pregnancy.

After implantation, embryonic stem cells undergo a process of ‘epigenetic priming,’ a necessary transition that allows these pluripotent cells to be receptive to signalling for differentiation into all of the cell types of the body. A hallmark of this priming event is the deposition of bivalent chromatin at a subset of promoters, marked by active H3K4me3 and repressive H3K27me3, poising them for activation (Bernstein et al. 2006). Failure to prime the embryonic genome results in developmental defects. The role for bivalent chromatin in placenta remains contentious (Rugg-Gunn et al. 2010; Andergassen et al. 2019; He et al. 2020) and hence is an important research question. The aim of this project is to characterise and test the functional importance of epigenetic priming in placental cells, linking poor priming to defects in placentation and consequences on foetal growth.

Using mouse as a model, this project will investigate the role for H3K4me3 methyltransferase MLL2, one of the key enzymes responsible for establishing bivalent chromatin (Denissov et al. 2014), in priming placental cells for differentiation.

Three important questions will be addressed:

1. What gene promoters are targeted by MLL2 during placental lineage specification?
2. What are the consequences of loss of MLL2 on the regulation of placental gene expression during development?
3. How does loss of MLL2 impact placental differentiation and function during pregnancy?

The student will obtain training in a wide variety of experimental techniques including next generation sequencing, histology, embryology and bioinformatics.

References

1. Bernstein B, Mikkelsen T, Xie X, Kamal M, Huebert D, Cuff J, Fry B, Meissner A, Wernig M, Plath K, et al. (2006) A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell 125:315-26.
2. Rugg-Gunn P, Cox B, Ralston A, Rossant J. (2010) Distinct histone modifications in stem cell lines and tissue lineages from the early mouse embryos. PNAS 107:10783-90.
3. Andergassen D, Muckenhuber M, Bammer PC, Kulinski TM, Theussl HC, Shimizu T, Penninger JM, Pauler FM, Hudson QJ. (2019) The Airn lncRNA does not require any DNA elements within its locus to silence distant imprinted genes. PLoS Genet 15.
4. He W, Wei Y, Gong X, Chang L, Jin W, Liu K, Wang X, Xiao Y, Zhang W, Chen Q, et al. (2020) Developmentally Delayed Epigenetic Reprogramming Underlying the Pathogenesis of Preeclampsia. BioRxiv. doi: https://doi.org/10.1101/2020.05.08.085290
5. Denissov S, Hofemeister H, Marks H, Kranz A, Ciotta G, Singh S, Anastassiadis K, Stunnenberg HG, Stewart AF. (2014) Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant. Development 141:526-37.