Epigenetics, DNA replication and the regulation of human height

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Project

80% of the factors explaining height variation in the human population are genetic. Surprisingly, some genes have a considerable influence on human height, influencing it by more than 2 cm. The genes involved modulate, among other things, the growth of bone and cartilage, and the activation and production of growth hormones.
Among the genetic variants affecting human height, several are located in the ZBTB38 gene sequence (Gudbjartsson et al., 2008). There are also pathological variants affecting ZBTB38 associated with severe growth retardation and short stature in adulthood (Clayton et al., 2013; Parsons et al., 2022). ZBTB38 is a zinc finger transcription factor capable of regulating the expression of many genes. The team is studying its function to reveal its mode of action on chromatin and its biological functions.

This project is in line with the thematic axes of the "OSCAR" rare bone, calcium and cartilage diseases health network and the Institute of Osteoarticular Diseases of the Université Paris Cité. This project started in the laboratory of Pierre-Antoine Defossez at the Epigenetics and Cell Fate center (UMR7216) in Paris, more here.

 

Our recent data show that :
- ZBTB38 is a protein regulated at the post-translational level by ubiquitination, which finely regulates its abundance in the cell (Miotto et al., 2014; Miotto et al., 2018).

- ZBTB38 binds to sequences in the genome with a particular, highly methylated DNA motif (Marchal et al. submitted).
- ZBTB38 regulates the expression of genes essential for cell proliferation and cell growth, such as the replication factor MCM10 or the cell cycle regulator CDKN1C (Miotto et al., 2014; Marchal et al., 2018).
- ZBTB38 plays an important role in prostate cancer. Its expression may serve as a predictive marker for recurrence and invasive cancer (de Dieuleveult et al., 2020).

- ZBTB38 regulates cellular metabolism, including the accumulation of reactive oxygen species (ROS), and susceptibility to certain chemotherapeutic agents that alter ROS levels (Miotto et al., 2018; de Dieuleveult et al., 2020).

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