Myriam Hemberger

Myriam Hemberger has located to Canada to take up a Professorship at the University of Calgary. Her new webpage can be found here.

Research Summary

The focus of our work is on the establishment, maintenance and differentiation of trophoblast cells leading to formation of a functional placenta. The placenta is the defining organ of most mammals, providing a nutritive conduit that is crucial for all embryonic development to occur. Trophoblast cells are the major building blocks of the developing placenta. They are the first cell type to arise very early in development when they are set apart from cells giving rise to the embryo itself. The various functions of trophoblast cells early in development are vital for reproductive success, as they lay the foundations for a normal pregnancy and healthy foetus later on. A better understanding of the mechanisms underlying these early events will be critical to develop better screens and therapeutic avenues for pregnancy complications.
 
We are in particular interested in how the early trophoblast niche is regulated by transcription factors and specific epigenetic modifiers to ensure normal development. Leading on from this, we also investigate how susceptible the trophoblast compartment is to perturbations by extrinsic factors that activate specific signalling cascades, including in the context of development in mothers of advanced age. For this we are taking a range of high-throughput epigenomic and transcriptomic approaches to study these early events in placental development.
 
Key among our tools is the use of murine trophoblast stem (TS) cells, which mimic many of the properties of the early placenta. Learning about the self-renewal mechanisms of TS cells, in comparison to embryonic stem (ES) cells, will help us uncover the fundamental principles of how the early placenta develops and is influenced by external factors, which may be predictive for life long physiology and health. These insights will also enable us to better understand the earliest steps in human placentation and to develop novel cellular research tools to study the underlying molecular processes.

Latest Publications

TET1 and 5-Hydroxymethylation Preserve the Stem Cell State of Mouse Trophoblast.
Senner CE, Chrysanthou S, Burge S, Lin HY, Branco MR, Hemberger M

The ten-eleven translocation factor TET1 and its conferred epigenetic modification 5-hydroxymethylcytosine (5hmC) have important roles in maintaining the pluripotent state of embryonic stem cells (ESCs). We previously showed that TET1 is also essential to maintain the stem cell state of trophoblast stem cells (TSCs). Here, we establish an integrated panel of absolute 5hmC levels, genome-wide DNA methylation and hydroxymethylation patterns, transcriptomes, and TET1 chromatin occupancy in TSCs and differentiated trophoblast cells. We show that the combined presence of 5-methylcytosine (5mC) and 5hmC correlates with transcriptional activity of associated genes. Hypoxia can slow down the global loss of 5hmC that occurs upon differentiation of TSCs. Notably, unlike in ESCs and epiblast cells, most TET1-bound regions overlap with active chromatin marks and TFAP2C binding sites and demarcate putative trophoblast enhancer regions. These chromatin modification and occupancy patterns are highly informative to identify novel candidate regulators of the TSC state.

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Stem cell reports, 1, 1, 13 May 2020

DOI: 10.1016/j.stemcr.2020.04.009

PMID: 32442533

Epigenetic changes occur at decidualisation genes as a function of reproductive ageing in mice.
Woods L, Morgan N, Zhao X, Dean W, Perez-Garcia V, Hemberger M

Reproductive decline in older female mice can be attributed to a failure of the uterus to decidualise in response to steroid hormones. Here, we show that normal decidualisation is associated with significant epigenetic changes. Notably, we identify a cohort of differentially methylated regions (DMRs), most of which gain DNA methylation between the early and late stages of decidualisation. These DMRs are enriched at progesterone-responsive gene loci that are essential for reproductive function. In female mice nearing the end of their reproductive lifespan, DNA methylation fidelity is lost at a number of CpG islands (CGIs) resulting in CGI hypermethylation at key decidualisation genes. Importantly, this hypermethylated state correlates with the failure of the corresponding genes to become transcriptionally upregulated during the implantation window. Thus, age-associated DNA methylation changes may underlie the decidualisation defects that are a common occurrence in older females. Alterations to the epigenome of uterine cells may therefore contribute significantly to the reproductive decline associated with advanced maternal age.

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Development (Cambridge, England), 147, 6, 17 Mar 2020

DOI: 10.1242/dev.185629

PMID: 32184271

Mechanisms of early placental development in mouse and humans.
Hemberger M, Hanna CW, Dean W

The importance of the placenta in supporting mammalian development has long been recognized, but our knowledge of the molecular, genetic and epigenetic requirements that underpin normal placentation has remained remarkably under-appreciated. Both the in vivo mouse model and in vitro-derived murine trophoblast stem cells have been invaluable research tools for gaining insights into these aspects of placental development and function, with recent studies starting to reshape our view of how a unique epigenetic environment contributes to trophoblast differentiation and placenta formation. These advances, together with recent successes in deriving human trophoblast stem cells, open up new and exciting prospects in basic and clinical settings that will help deepen our understanding of placental development and associated disorders of pregnancy.

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Nature reviews. Genetics, , 1471-0064, 2019

PMID: 31534202