Sex-Determination as a model to understand developmental gene regulation – SexGenReg

The objectives of this proposal are to define key gene regulatory elements (GREs) and gene regulatory networks (GRN) that govern cell fate choice decisions during human sex-determination (SD). Mammalian SD is a tightly controlled and highly complex process where the bipotential gonad anlage forms either a testis or an ovary. This process is governed by poorly understood mutually antagonistic gene regulatory pathways. We have identified several genetic factors involved in SD. However, the genetic hierarchy and how these GRNs interact to repress one cell fate whilst promoting the other remains to be determined. Errors in human testis-determination result in the rare phenotype of 46,XY gonadal dysgenesis. Our research indicates that only 50% of these cases can be explained by pathological variants in coding sequences. Our recent data indicate, unlike other congenital disorders, the phenotype in these patients is due to variants in GREs. This project aims to define functionally relevant GREs and GRNs in sex-determination using a multidisciplinary approach combining human genomics on rare disease, computational analysis, and mouse models. We will also use a human testis organoid model that we have recently developed that recapitulates human in vivo testis-determination and that can successfully model pathogenic enhancer variants. Defining the GRE/GRNs controlling SD, and defining genetic variants that disrupt this process, will provide a general model of the regulation of gene expression and cell fate decisions.