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An Evolutionary Approach to Understanding Transcriptional Control in the Human Placenta Co-supervised by Dr Paul Flicek, European Bioinformatics Institute (EBI, Hinxton)

An Evolutionary Approach to Understanding Transcriptional Control in the Human Placenta  Co-supervised by Dr Paul Flicek, European Bioinformatics Institute (EBI, Hinxton)

Background.

Pregnancy is a unique state which involves the interaction between two genomes. This interaction is mediated through the placenta. 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. We aim to create a map of evolutionarily conserved placental regulatory sequences 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 investigate the placental regulatory network to identify mammalian conserved and lineage specific aspects.  These will be created by comparing genome wide chromatin immunoprecipitation (ChIP-seq) maps identifying key regulatory regions from human and several other model species using methods previously applied to liver tissue (Schmidt et al. 2010; Villar et al. 2015).

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 special and intensive care records.  The richness of this data allows us to identify and rigorously define cases where the baby is small for gestational age, effected by pre-eclampsia or gestational diabetes.

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 question which will also be of clinical benefit in the future.

For further information, please contact:

Steve Charnock-Jones, dscj1@cam.ac.uk or

Paul Flicek, flicek@ebi.ac.uk

Schmidt, Dominic, Michael D Wilson, Benoit Ballester, Petra C Schwalie, Gordon D Brown, Aileen Marshall, Claudia Kutter, et al. 2010. “Five-Vertebrate ChIP-Seq Reveals the Evolutionary Dynamics of Transcription Factor Binding..” Science (New York, NY) 328 (5981): 1036–40. doi:10.1126/science.1186176.

Villar, Diego, 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 (3): 554–66. doi:10.1016/j.cell.2015.01.006.