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Department of Physiology, Development and Neuroscience

The Watson lab studies transgenerational epigenetic inheritance of congenital malformations caused by abnormal folate metabolism.

Biography

Dr Watson completed her PhD in Biochemistry and Molecular Biology at the University of Calgary (Canada) in 2008. She was awarded the Next Generation Fellowship by the Centre for Trophoblast Research in 2009 to undergo an independent research programme at the Department of Physiology, Development and Neuroscience (PDN, University of Cambridge). Her research focused on the molecular mechanisms of transgenerational epigenetic inheritance in a mouse model of abnormal folate metabolism. She was hired as a Lecturer (Assistant Professor) to continue this research in 2013, and soon afterwards was awarded the Lister Research Prize (Lister Institute of Preventative Medicine). As an Associate Professor in PDN (2021-current), she continues her research on how congenital malformations are inherited over multiple generations without genetic mutation. The current research focus of her research is on the epigenetic patterns (e.g., DNA methylation, histone modifications) and cytoplasmic content (e.g., proteins, small non-coding RNA) in germ cells that influence transcriptional pathways in the early embryo to increase phenotypic risk in the immediate offspring and over multiple generations. In doing so, her lab also explores the molecular mechanism of folate metabolism during metabolism, the details of which have eluded researchers for decades. Dr Watson is on the Board of Managers for the Centre for Trophoblast Research, is a Fellow and Assistant postgraduate tutor at Newnham College (Cambridge), and is co-course organiser for MST Part IB Human Reproduction and Part II Module P2 Development and Stem Cells.

Research

Epigenetic changes accrued in the genome throughout one’s lifetime can contribute to an increased risk for disease. These changes may occur through exposure to environmental stressors (e.g., toxins, nutrient deficiency, etc.) that alter epigenetic factors, such as patterns of DNA methylation, ultimately causing gene misexpression. Exposure to these environmental factors in utero may alter epigenetic programming, such that the nine months before you are born may have a profound impact on your health later in life. Mounting evidence also indicates that maternal, paternal or even grandparental exposure may contribute to congenital malformations and/or metabolic and cardiovascular diseases in children and grandchildren. This non-conventional inheritance occurs via epigenetic rather than genetic inheritance, and implicates the germline. Very little is understood regarding transgenerational mechanisms of inheritance. Our aim is to explore how developmental abnormalities and disease risk is epigenetically transmitted between generations. Further understanding this mechanism will drastically impact human health.

Transgenerational epigenetic effects of folate metabolism

The Watson lab currently explores the mechanisms behind the transgenerational epigenetic effects of folate metabolism during fetal and placental development. Folate is a vitamin important for the one-carbon metabolism and methylation of cell components (e.g., DNA). To study this, they use a genetic mouse model with a mutation in a key gene involved in folate metabolism (Mtrrgt) that disrupts folate metabolism and results in similar metabolic effects as human folate deficiency. They recently showed using highly controlled genetic pedigrees that when either maternal grandparent carried the Mtrrgt mutant allele, it was sufficient to cause developmental abnormalities and epigenetic instability in their grandprogeny at midgestation (Padmanabhan et al, 2013 Cell). This occurred even when the mother and the grandprogeny are genetically wildtype for the Mtrr mutation. Some of the abnormalities (e.g., neural tube, heart and placental defects) persisted after embryo transfer experiments and for up to 5 generations, implicating epigenetic inheritance as a mechanism.

The goal of their current research goal is to use the Mtrr mouse model to understand the molecular mechanism behind the transgenerational effects of folate metabolism on development by breaking it down into the specific properties of each generation (i.e., grandparental, maternal and placental/embryonic effects) using epigenetic, molecular and embryo manipulation techniques. Ultimately, this will help us explain the role of folate metabolism during development and provide clues as to how transgenerational inheritance of disease and phenotypes is achieved.

Publications

Key publications: 

Wilkinson AL, Menelaou K, Rakoczy J, Tan XS, Watson ED, (2021), Disruption of folate metabolism causes poor alignment and spacing of mouse conceptuses for multiple generations, bioRxiv preprint, doi.org/10.1101/2021.06.11.448112

Bertozzi TM, Becker JL, Blake GET, Bansal A, Nguyen DK, Fernandez-Twinn DS, Ozanne SE, Bartolomei MS, Simmons RA, Watson ED, Ferguson-Smith AC, (2021), Variably methylated retrotransposons are refractory to a range of environmental perturbations, Nature Genetics, 53(8): 1233-42

Capatina N, Hemberger M, Burton GJ, Watson ED*, Yung HW*, (2021), Excessive endoplasmic reticulum stress drives aberrant mouse trophoblast differentiation and placental development leading to pregnancy loss, The Journal of Physiology, 599(17): 4153-81 (*Equal contribution)

Blake GET, Zhao X, Yung HW, Burton GJ, Ferguson-Smith AC, Hamiliton RS, Watson ED, (2021), Defective folate metabolism causes germline epigenetic instability and distinguishes HIRA as a phenotype inheritance biomarker, Nature Communications, 12(1): 3714

Sowton A, Padmanabhan N, Tunster SJ, McNally B, Murgia A, Yusuf A, Griffin JL, Murray AJ, Watson ED, (2020), Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice, Molecular Genetics and Metabolism Reports, 23: 100580 

Tunster SJ, Watson ED, Fowden AL, Burton GJ, (2020), Placenta glycogen stores and fetal growth: evidence from genetic mouse models, Reproduction, 159(6): R213-R235

Menelaou K, Prater M, Tunster SJ, Blake GET, Geary Joo C, Cross JC, Hamilton RS, Watson ED, (2020), Blastocyst transfer in mice alters the placenta transcriptome and growth, Reproduction, 156(2): 115-132

Blake GET, Hall J, Petkovic GE, Watson ED, (2019), Analysis of spermatogenesis and fertility in adult mice with a hypomorphic mutation in the Mtrr gene, Reproduction, Fertility and Development 31(11): 1730-1740 

Padmanabhan N, Menelaou K, Gao J, Anderson A, Blake GET, Li T, Daw BN, Watson ED, (2018), Abnormal folate metabolism causes age-, sex-, and parent-of-origin specific haematological defects in mice, The Journal of Physiology, 596(18): 4341-60

Padmanabhan N, Rakoczy J, Kondratowicz M, Menelaou K, Blake GET, Watson ED, (2017), Multigenerational analysis of sex-specific phenotypic differences at midgestation caused by abnormal folate metabolismEnvironmental Epigenetics, 3(4): 1-17

Rakoczy J, Padmanabhan N, Krzak AM, Kieckbusch J, Cindrova-Davies T, Watson ED, (2017), Dynamic expression of TET1, TET2, and TET3 dioxygenases in mouse and human placentas throughout gestationPlacenta, 59: 46-56

Blake GET, Watson ED, (2016), Unravelling the complex mechanisms of transgenerational epigenetic inheritance, Current Opinion in Chemical Biology, 33: 101-7

Watson ED, Rakoczy J, (2016), Fat eggs shape offspring health, Nature Genetics, 48: 478-9

Watson ED, (2016), Transferring fragments of paternal metabolism to the offspring, Cell Metabolism, 23(3): 401-2

Padmanabhan N, Jia D, Geary-Joo C, Wu X, Ferguson-Smith AC, Fung E, Bieda M, Snyder FF, Gravel RA, Cross JC, Watson ED, (2013), Mutation in folate metabolism causes epigenetic instability and transgenerational effects on development, Cell, 155(1): 81-93

Teaching and Supervisions

Teaching: 

Course co-organiser, Part IB Human Reproduction

Module co-organiser, Part II Module P2 Development and Stem Cells

Part IB Veterinary Reproductive Biology

Part IB NST Physiology

Supervisor, Part IA Functional Anatomy of the Body: Human Embryology (Newnham College)

Research supervision: 

Current lab members

Dr Claire Senner (Next Generation Fellow, CTR)

Charlotte Handford (PhD student [co-supervised by Magdalena Zernicka-Goetz], CTR studentship)

Amy Wilkinson (PDN Part II student)

 

**We are recruiting a postdoc! Details are to come. Please email Dr Watson for information**

***Prospective graduate students, please email Dr Watson***

Other Professional Activities

College Activities

Fellow and Assistant postgraduate tutor, Newnham College

 

Editorial Board Member

Associate editor, Reproduction

Editorial review board member, Environmental Epigenetics

Associate Professor in Reproductive Biology
Dr Erica D Watson

Contact Details

+44 (0) 1223 333858
Email address: 

Plain English

We are trying to figure out how our environment affects the development of our grandchildren. For example, we know that a poor diet can alter how our genes are expressed and increase our risk for disease. Epigenetics is a layer of instructions that tells a cell how to control gene expression. This involves changes in chemicals called methyl groups that attach to DNA or RNA and flip their 'on/off' switch. We are interested in understanding how folic acid deficiency in particular alters epigenetics of cells to cause defects in maternal physiology and fetal and placental development. We are trying to understand what epigenetic changes are made in these cells and whether these changes can be passed from one generation to the next."

 

Above: Mouse embryo and placenta at embryonic (E) day 10.5.