Role of TRIM28 in maintenance of ovarian identity and primary sex-determination – SexMaintain
In vertebrates, the embryonic gonad prior to sexual differentiation is a bi-potential tissue where every cell population of progenitors can be engaged in two alternative fates: ‘male’ or ‘female’. In mammals the presence of the Y chromosome initiates a genetic cascade in the embryonic gonad that leads to the differentiation of the male supporting cells, the Sertoli cells. In the female gonad, in the absence of the Y chromosome, the supporting cell progenitors differentiate into granulosa cells. The testicular and ovarian supporting cells have a crucial role for the adult reproductive organs: they ensure that the germinal lineage achieves successfully sperm or oocyte production.
In recent years the concept of maintenance of gonadal identity has emerged. That is, various key genes must stay active in the adult gonad to prevent spontaneous reprogramming into the opposite sex identity. For instance, the ablation of the FoxL2 gene in adult female mice induced the reprogramming of granulosa cells into Sertoli cells. In this case, ovarian cells take the cell fate of their testicular ‘equivalent’ cells. Conversely, the knock-out of the Dmrt1 gene in the adult testis induces the reprogramming of Sertoli cells into granulosa cells. So, it seems that the bipotential capacity of the embryonic gonad remains in the adult organ, raising the question of the molecular mechanism(s) behind the maintenance system. The phenotypic stability of the supporting cells is crucial for the reproductive function: the correct progression of gametogenesis requires a perfect match between the molecular "sexes" of the supporting cells and the germinal lineage, otherwise a mismatch will cause sterility.
Recently, we discovered that the protein TRIM28 is a new player in the maintenance of the identity of the adult ovary. Indeed, the knock-out in mice of Trim28 in granulosa cells induced their reprogramming to a Sertoli cell fate. Unlike FOXL2 or DMRT1, the TRIM28 protein is not a transcription factor harboring DNA-binding capacity, but a protein able to bind chromatin where it will build protein complexes, having multiple features such as DNA damage response, control of genomic imprinting, transcriptional repression and pausing. This discovery provides a new entry point into the black box of a crucial mechanism for mammalian reproduction: TRIM28 could be an integrating factor, loaded onto the chromatin of its target genes and would be able to mediate effects of transcription factors such as FOXL2.
With the SexMaintain project we aim to decipher the role of TRIM28 in the biology of mammalian reproduction. We will use in vivo and in vitro approaches with the help of two complementary models that are the mouse, for the strength of the available of genetic tools, and the goat for its physiological proximity to humans. Thus, we will study the role of TRIM28 in the maintenance of granulosa cell identity by analyzing of genetic networks under its control and deciphering the molecular mechanisms triggered by the action of TRIM28 to suppress the testicular program in the ovary.
Beyond the capacity to help blocking the male program in adult ovary, we will also analyze the role of TRIM28 as a potential switch in the primary sex determination mechanism of the embryonic gonad.
Finally, we will take advantage of the discovery of TRIM28 as a new player of reproductive biology to screen for mutations of this gene in patients suffering from disorders of sexual development and primary ovarian insufficiency.
Monsieur Francis POULAT (INSTITUT DE GENETIQUE HUMAINE)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
IGH INSTITUT DE GENETIQUE HUMAINE
IJM Institut Jacques Monod
Help of the ANR 584,076 euros
Beginning and duration of the scientific project: September 2016 - 36 Months