B3580 - Investigating the Activity of Transposon-Derived Regulatory Sequences in the Human Placenta - 04/08/2020

B number: 
Principal applicant name: 
Jennifer Frost | Queen Mary University of London (UK)
Dr Miguel Branco
Title of project: 
Investigating the Activity of Transposon-Derived Regulatory Sequences in the Human Placenta
Proposal summary: 

The placenta is crucial for the initiation and maintenance of pregnancy. Common complications of human pregnancy, such as preeclampsia, often have unknown etiology but feature contributions from genetic and non-genetic causes. DNA exists in the cell bound by proteins and other molecules, forming a structure known as chromatin. The structural conformation of chromatin is just as important as the DNA code itself, since chromatin structure dictates which components of DNA are active, and therefore able to regulate the cell. Formalin-fixed placentas maintain the structural conformation of their chromatin, making them a uniquely valuable resource to identify the location and activity of regulatory DNA. My proposal seeks to investigate the causes of preeclampsia by comparing the chromatin structure in formalin-fixed placentas from control pregnancies and those complicated with preeclampsia. I will focus on regions of non-coding DNA that regulate gene activity, so-called gene promoters and enhancers, including a special subset of these regions known as transposons. Placental chromatin exhibits a unique structure compared to other tissues, featuring an open conformation around transposons, indicative of their activity in placenta. The activity of gene-regulatory DNA provides the basis of tissue and organ-specific developmental programs. As such, the development and function of the placenta is dictated by the activity of regulatory DNA, and structural variation at these regions can cause disease. I will test the hypothesis that chromatin structure variation of DNA regulatory sequences contributes to the causes of preeclampsia.

Impact of research: 
This research will provide proof-of-principal that archived placental samples can provide information on the gene regulatory status of the genome of the sample. Further, there will be a direct impact of the data provided from the samples in this study, in the identification of non-coding regulatory regions that are potentially involved in preeclampsia. This would lead to future expansion of the study into related pregnancy complications such as fetal growth restriction, pre-term birth, and recurrent miscarriage. This study will provide candidate genomic sequences for future research, as well as genetic screening and therapy in two ways: Most disease associated sequence variation is found in non-coding regions, and our data will be an important resource, revealing non-coding candidate regulatory regions impacted by epigenetic variation, which indicates that their genetic variation may also be disease-causing. In the future it will be key to investigate the presence of SNPs in candidate regulatory regions that we identify, which may alter transcription factor binding sites, for example, affecting gene expression. Secondly, the proposal investigates epigenetic variation between preeclampsia and controls, variation that is potentially impacted by environmental conditions and uniquely amenable to therapeutic intervention. Finally, by focusing our analysis on transposons, which are highly repetitive regions and poorly understood, this project will elucidate novel candidate genes and regulatory pathways that may contribute to the pathogenesis of preeclampsia.
Date proposal received: 
Thursday, 23 July, 2020
Date proposal approved: 
Thursday, 23 July, 2020
Developmental biology, Fertility/infertility, Pregnancy - e.g. reproductive health, postnatal depression, birth outcomes, etc., DNA sequencing, Chromatin immunoprecipitation, Biological samples -e.g. blood, cell lines, saliva, etc., Birth outcomes, Development, Epigenetics, Expression, Genetic epidemiology, Genomics, Growth, Mothers - maternal age, menopause, obstetrics