Oral Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Determining the role of maternal epigenetic inheritance in bone development and disease (#31)

Ruby Oberin 1 , Heidi Bildsoe 1 , Tesha Tsai 1 , Natalie A Sims 2 3 , Patrick Western 1
  1. Hudson Institute of Medical Research, Clayton, VICTORIA, Australia
  2. St. Vincent’s Institute of Medical Research, Fitzroy , Vic, Australia
  3. Department of Medicine at St. Vincent’s Hospital, The University of Melbourne, Fitzroy , Vic, Australia

Exposure of the developing germline to environmental factors, such as diet and drugs, is thought to alter epigenetic programming in gametes and modify development, phenotype, and disease heritability in offspring. Embryonic Ectoderm Development (EED) is an essential subunit of the epigenetic modifier Polycomb Repressive Complex 2, which regulates genes controlling cell differentiation in bone, brain and haemopoiesis. In humans, germline mutations in EED result in Cohen-Gibson syndrome, characterized by fetal overgrowth, accelerated bone aging and skeletal defects. Whilst the role of EED in stem cell differentiation and development is well understood, its role in epigenetic programming of the oocyte and its consequent influence on offspring development is poorly understood.

To determine the role of EED in oocyte programming and epigenetic inheritance, we developed a mouse model in which Eed is specifically deleted in growing oocytes. This model facilitates the production of genetically identical heterozygous offspring from oocytes with differences in their epigenetic heritage. We predicted that offspring from oocytes lacking EED would have impaired bone development, as well as compromised bone maintenance and repair.

Heterozygous offspring produced from the oocytes lacking EED-dependent epigenetic programming exhibited increased bone length and greater bone mineral density compared to genetically identical heterozygous controls that retained programming. MicroCT analyses identified an 10% increase in mineralised bone length and 15% increase in mineralised bone width. Histological analyses revealed this was associated with lengthening of the growth plate hypertrophic zone, indicating fetal overgrowth due to accelerated bone development. This indicates that altered EED-dependent epigenetic programming in the oocyte has consequences for offspring bone development and phenotype, and provides a model of the skeletal defect associated with Cohen-Gibson syndrome.  This model will be used to identify how inherited epigenetic information controls early life and long-term skeletal development, which is crucial for understanding the developmental origins of disease.

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