Gestational ageing in the placenta

Characterising the epigenome of the human placenta

Summary

Project Summary.

Led by:

David Monk, UEA School of Biological Sciences

Research Team:

UEA School of Biological Sciences

Earlham Institute Macaulay and Haerty Groups

Earlham Institute Genomics Pipelines

Funded by:

UKRI Biotechnology and Biological Sciences Research Council BB/V016156/1

The human placenta links a growing baby to its mother, providing oxygen and nutrients while removing waste and carbon dioxide. If this vital organ does not develop or function correctly, the consequences can be significant.

In order to understand what happens when things go wrong, we must first understand normal development. Gene expression dictates which cells are produced where in the placenta and how those cells behave over time.

Expression is regulated by various modifications to both the DNA and the scaffolding structures which hold it in place. These modifications are epigenetic – molecular additions which do not change the DNA code itself but do change the way the code behaves. As yet, there has been no systematic characterisation of the normal epigenetic modifications in the placenta during development.

One of these epigenetic modifications involves bolting molecules, known as methyl groups, onto specific sites in the DNA. This modification is called methylation and directly impacts gene expression - how much the DNA will ultimately be expressed as proteins or other functional molecules, such as regulatory RNA.

This project will paint a very detailed picture of methylation in the placenta, from early to late pregnancy, and how this might impact gene expression and influence other epigenetic marks.

The work involves a series of experiments to assess changes in the placental epigenome throughout gestation. The intention is to create an exhaustive profile of the placenta’s development, which can be used as a basis for comparison in later biomedical research.

Detail

Details.

Epigenetic modification

There are many different kinds of epigenetic modifications. Addition of a methyl group during methylation tends to turn genes “off” - they stop expressing - while removal turns them “on” - they begin to express again. The placenta has significantly less DNA methylation than all other tissues in the human body and contains hundreds of unique imprinted genes which are only turned “on” in either the maternal or paternal copy, rather than both.

In a cell nucleus, DNA is wrapped around proteins called histones, forming a molecule known as chromatin. Histones are also subject to epigenetic modification, which affects how tightly wrapped the chromatin is and subsequently how much transcription occurs. These epigenetic processes are dynamic. Where, when, and for how long they impact DNA during gestation remain to be explored.

Collaborative expertise

At the Earlham Institute, we will be using our single-cell and bioinformatics experience and expertise to make the best use of this vast amount of data. Working closely with our collaborators at UEA, we will be analysing the sequencing and epigenetic data both from bulk samples and single-cell experiments.

Tissues like the placenta are made up of many different kinds of cells, each with their own particular expression profiles. Since variation is likely, isolated single cells will also be profiled using EI’s advanced single cell and spatial genomics platforms. This gives researchers a greater chance to identify patterns unique to specific cells, as well as the higher resolution necessary to experimentally test ideas about the mechanisms underpinning this epigenetic regulation work.

Placenta-derived data will be compared across time and within different cells, allowing the identification of regions important for expression changes as the placenta ages during gestation. Imprinted genes will also be assessed by looking at family trios of maternal, paternal, and placental sequencing data. The Institute’s Genomics Pipelines team will also be undertaking sequencing work for the project, with our collaborators at the University of East Anglia (UEA) taking the lead in wet lab experiments across a broad range of cutting-edge epigenetic and transcriptomic technologies.

This collaborative project involves researchers from UEA, the Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich Research Park Biorepository, and several different teams at the Earlham Institute.

2019-Norwich-Research-Park-aerial-edited-(1)23

Image: This project utilises expertise and facilities from across the Norwich Research Park, pictured above.

Collaborators

Impact statement.

The group is planning to produce consensus epigenetic maps for early and late placenta samples. These datasets will allow the identification of these important functional regulatory elements, many of which are anticipated to change during gestation.

Bioinformatic analyses could reveal the temporal epigenetic and expression profiles for imprinted genes. This will allow novel regulatory elements to be defined and characterised.

In the longer term, this project will generate large amounts of novel data, allowing the visualisation of the placenta epigenome on an unprecedented scale. This data will have wide-ranging potential biomedical applications.