Page Laboratory: Sex Differences in Health and Disease

The Page Lab’s long-term goal is to understand, at the molecular level, the differences and similarities between males and females throughout the body, in health and disease.  This understanding of where male and female cells, tissues, and organs are essentially the same and where they are fundamentally different is a critical and overlooked facet of the teaching and practice of medicine and the conduct of biomedical research.

Many debilitating diseases, including heart failure, systemic lupus, autism spectrum disorder, and many cancers, show striking yet unexplained sex biases in prevalence and severity.  Such biases have historically been attributed entirely to cell-extrinsic factors, such as sex hormones or environment.  For a number of reasons, the medical and biomedical research community have long ignored the multifaceted function and impact of the X and Y chromosomes (the sex chromosomes).  The resulting blind spot means that biomedicine has little knowledge of the regulatory capacities and specific effects of sex chromosomes, or of the potentially widespread molecular differences—and health implications—that result from being male (XY) or female (XX).

Recent advances by the Page Lab provide an intellectual framework for studying these fundamental questions.  Through comprehensively sequencing sex chromosomes across multiple mammalian species, the Page Lab discovered that a group of genes on the sex chromosomes encode master transcriptional and epigenetic regulators, which control how cells turn genes on and off throughout the genome.  The fact that the X version is expressed in females and both the X and Y versions are expressed in males implies that gene activity across the genome is controlled differently in XX and XY cells.  The resulting female- and male-specific regulation of the genome likely affects all dimensions of human biology, including how disease susceptibility varies between males and females in both severity and incidence.

The Page Lab has embarked on a long-term, integrated program of scientific research, with the goal of understanding, at the genomic, epigenetic, molecular, and cellular levels, the contributions of the sex chromosomes to sex differences in health and disease.  This program involves a network of collaborators, with the Page Lab serving as the hub, which expands their basic science investigations and pursues translational research and development.  The lab is currently pursuing multiple parallel and interactive investigative tracks:

• Comprehensively cataloguing molecular-level function of XX vs. XY chromosome constitutions in human tissues and in animal models traditionally used in basic research and drug development—creating a definitive “dictionary of molecular function” for sex chromosomes.

• Discovering the differential impact of sex chromosome variations across the body—by cataloguing and deeply analyzing molecular-level function and resulting phenotypes in females and males who, collectively, possess a wide range of sex chromosome constitutions.

• Exploring molecular-level variations in organs and systems where many diseases with sex-based differences manifest—notably the immune system, heart, and brain—and identifying specific mechanisms underlying the X and Y chromosomes’ respective effects on health and disease.