Engel Lab awarded NSF grant to study sex differences during embryonic development

Abstract

Beginning at the earliest stages of embryonic life, sex chromosomes program autosomal gene expression and the epigenomic landscape and establish sex-specific gene networks. The molecular mechanisms by which sex chromosome-linked genes imprint the autosomes with sexual identity is not known. Also unknown is how sex-biased gene expression evolves across development and in different lineages. The objective of this proposal is to fill these crucial knowledge gaps by integrating experimental and systems level analyses in vitro and in vivo. We hypothesize that regulatory factors encoded on the sex chromosomes dictate the differential expression and chromatin status of autosomal genes in the embryo. Whereas some of these are compensated or equalized, others persist, affecting cellular phenotypes even in the adult organism. Thus, male and female cellular identities are first programmed into the genome well before sex hormones appear. To test our hypothesis, we propose the following: 1) to determine the transcriptional and epigenetic effects of sex-biased regulatory factors in early embryogenesis; and 2) to identify the sex chromosome-dependent biases in gene expression and epigenetic patterns before and after the appearance of sex hormones. While many studies on sexual dimorphisms focus on hormonal influence, we posit that the sex chromosomes contribute to gene expression and epigenetic differences that persist across the lifespan. Developmental studies have recently been undertaken in non-mammalian model systems, revealing sex-biased gene expression at all stages, despite expectations that sexual dimorphisms only appear after gonad formation. No such studies have been performed in mammals. Our studies address this gap by characterizing the mechanisms by which sex biases wax and wane during development, even in stages with no conspicuous phenotypic dimorphisms. Since epigenetic marks established in early development can be latent and relevant to gene expression at later stages, this research will also serve as a paradigm for how events in embryogenesis influence dimorphisms after birth and beyond. Moreover, our studies will lay the groundwork for mechanistic studies on the effects of transcription and epigenetic factor dosage on the transcriptome.