An Evolutionary Approach to Understanding Transcriptional Control in the Human Placenta

An Evolutionary Approach to Understanding Transcriptional Control in the Human Placenta

EBPOD 2017: Project 11

This is one of 11 joint postdoctoral fellowships offered by EMBL-EBI, the NIHR Cambridge Biomedical Research Centre and the University of Cambridge’s School of the Biological Sciences in 2017.

Principal Investigators

  • Prof. D. Stephen Charnock-Jones (Professor of Reproductive Biology, Dept Obstetrics & Gynaecology. University of Cambridge).
  • Dr Paul Flicek, Group Leader and Senior Scientist. European Bioinformatics Institute (EMBL-EBI).
  • Prof. Graham J Burton (Dept Physiology, Development and Neuroscience. University of Cambridge).

Background

Pregnancy is a unique state which involves the interaction between two genomes. This interaction is mediated through the placenta, a characteristic mechanism shared by all placental mammals. Complications of pregnancy determine 5-10% of the global burden of disease. Despite its importance, our understanding of the control of gene function in both health and disease is sparse. To address this we aim to create a map of evolutionarily conserved placental regulatory regions and compare this network to a unique sample set from well defined patients. The sequence data we have and are collecting is suitable for chromatin, DNA and RNA bioinformatics analysis.

Experimental approach

We will generate genome wide chromatin immunoprecipitation (ChIP-seq) maps identifying key regulatory regions from placental tissue from human and several other mammalian species using methods previously applied to liver (Villar et al. 2015). By comparing the genomic locations of enhancers and promoters across species, we will be able to identify evolutionary conserved and lineage specific transcriptional regulatory regions active in placenta. The anatomy of the placenta is very variable with the 3 types (epitheliochorial, endotheliochorial and haemochorial) being widely dispersed across multiple phyla. Despite the anatomical diversity we have shown that in the yolk sac functional modules of genes carrying out specific sets of functions are present (Cindrova-Davies et al 2017). This dichotomy suggests that vital placental functions will be apparent in both the conserved and lineage-specific regulatory networks. The work proposed in this project will elucidate the transcriptional control mechanisms that may underlie this.

The resulting information about transcriptional regulation in the placenta will be used in the analysis of molecular data arising from our prospective cohort study (POPs) of 4,512 pregnant nulliparous women attending the Rosie Hospital Cambridge for antenatal care. We have deep phenotyping data: maternal and paternal characteristics, antenatal ultrasound scans (4 time-points in pregnancy), the delivery unit record, all the laboratory investigations, and the neonatal and intensive care records. Sample collection is complete and we have maternal, paternal and infant DNA and multiple placental samples suitable for additional chromatin, DNA and RNA analysis. The richness of this data allows us to identify and rigorously define cases where the baby is small for EMBL-EBI Biomedical PostDoctoral Fellowships (EBPOD) gestational age (SGA), effected by pre-eclampsia (PE) or gestational diabetes (GDM). Critically, we can pair the cases with normal healthy controls matched for maternal and obstetric characteristics (Sovio 2015) and we can investigate to whether specific regulatory regions are associated with specific complications.

For example, we have already generated total and short RNA-Seq data (~100M and ~25M reads respectively) from 55 SGA and 94 PE cases and their matched controls (ie 298 samples). We also have whole genome bisulphite sequencing data on a small number (8 in total).

Relevance to biology and/or health and disease

Adverse outcomes of pregnancy, such as growth restriction, stillbirth, pre-eclampsia and prematurity cause significant morbidity and mortality; in the UK 10-12% of pregnancies miscarry and there are approximately 4,000 stillbirths each year. In addition, they place considerable economic and emotional burdens on society. The complications that lead to stillbirth are also associated with infant mortality, disability and, through a poor prenatal environment, ill health in later life. However, the underlying cause of placental dysfunction leading to these complications remains obscure.

Bringing an evolutionary analysis to provide insight in the molecular data of this study is unique as is the deep phenotyping of this cohort. Within the cohort, the ability to do 1-to-1 matching of cases and controls adds more power to the study. Hence, elucidation of the mechanisms underlying transcriptional control of placental function will address fundamental biological questions which will also be of clinical benefit in the future.

References

  1. Tereza Cindrova-Davies, Eric Jauniaux, Michael G. Elliot, Sungsam Gong, Graham J. Burton, D. Stephen Charnock-Jones. 2017. RNA-Seq reveals conservation of function among the yolk sacs of human, mouse and chicken. PNAS, Under revision.
  2. Ulla Sovio, Ian R White, Alison Dacey, Dharmintra Pasupathy, and Gordon C S Smith. 2015. Screening for Fetal Growth Restriction with Universal Third Trimester Ultrasonography in Nulliparous Women in the Pregnancy Outcome Prediction (POP) Study: a Prospective Cohort Study. Lancet 386: 2089–97. doi:10.1016/S0140-6736(15)00131-2.
  3. Diego Villar, Camille Berthelot, Sarah Aldridge, Tim F Rayner, Margus Lukk, Miguel Pignatelli, Thomas J Park, et al. 2015. Enhancer Evolution Across 20 Mammalian Species. Cell 160: 554–66. doi:10.1016/j.cell.2015.01.006.