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Publications of the Week

Sex Differences in Gene Expression and Regulatory Networks across 29 Human Tissues

By July 7, 2020No Comments

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This week we profile a recent publication in Cell Reports from the laboratory
of Dr. Dawn DeMeo (pictured) at Harvard Medical School.

Can you provide a brief overview of your lab’s current research focus?

Dr. DeMeo is an Associate Professor of Medicine at Harvard Medical School and a Faculty Member at Brigham and Women’s Hospital Division of Medicine, in the Channing Division of Network Medicine and Pulmonary and Critical Care Divisions. As a trained pulmonologist and critical care physician, she has had a long-standing interest in genetics and epigenetics as they relate to overall health and disease, with an emphasis on lung health and advanced lung diseases, particularly chronic obstructive pulmonary disease (COPD). Dr. DeMeo’s team addresses a range of questions focused on sex and gender differences that start with careful large-scale epidemiology and proceed to genetic modeling. Given the importance of sex and gender differences for advancing human health, Dr. DeMeo has studied lung disease as an exemplar for investigating the molecular differences relevant to sex and gender differences in health, aging, and diseases in general. To do this, we are studying gene regulatory differences at a network level, as well as differences in the epigenome that may be observable starting in utero and recapitulate across the life course and further impacted by environmental and personal exposures (such as smoking and vaping). Dr. DeMeo’s vision includes translating scientific discovery to effective multidisciplinary care for maintaining the health of boys/men and girls/women throughout the life-course.

What is the significance of the findings in this publication?

This study provides a first glimpse into gene regulatory network processes that differ by sex for many human tissues; these observations provide new insights into processes that may alter disease risk, development, and responses to treatments for each sex. A major point is that although they did not observe extreme differences in autosomal gene expression between males and females, there were significant differences in the gene targeting when modeling genes in a network framework. Scientists have long known that these differences, in part, are reflected by genes that are “turned on” or “turned off” in each sex but have not understood how this happens. In the study published in Cell Reports, the authors modeled the network of factors that control gene expression and observed that these factors act differently between men and women. By analyzing gene regulatory networks in twenty-nine tissues, they found sex differences in the network structure, and showed that differential targeting of genes by sex occurs in most tissues. Differential gene regulation by sex is associated with many biological processes and highlights genes related to diseases with recognized sex-biased manifestations, such as Parkinson’s disease, Alzheimer’s disease, diabetes, and cardiomyopathy. Exploring sex differences is crucial not only for understanding biological sex differences but also for guiding the best therapeutic strategies in men and women; network based approaches as applied here provide a more holistic and less reductionistic approach for understanding sex and gender differences. Addressing sex and gender differences in molecular studies of health and disease is a cornerstone for scientific and medical innovation, and these findings “underline the importance of considering systems-level differences” to understand trends observable by studying careful epidemiology. This study also highlights the paramount importance of collaborative and multidisciplinary teams of researchers needed to translate “Big Data” analyses to potential public health insights.

What are the next steps for this research?

We are current exploring improved modeling of X and Y chromosome data and how best to incorporate sex chromosome data into network models. We are also applying our network-based approach to diseases such as colon, lung and pancreatic cancers, COPD, Alzheimer’s disease and sex difference in development and aging. Many diseases affect men and women differently, and understanding the sex-based and gender-influenced differences will move precision medicine forward. We have understood this for many years for cardiovascular disease, but we believe if we take the time to explore we will see these differences matter starting at the molecular level, for all organ systems and diseases.

This work was funded by:

Our research team has been funded by the National Institutes of Health. In addition, Dr. DeMeo is currently funded by grants from the Alpha-1 Foundation and a special award from the Brigham and Women’s Hospital First-in-Women Precision Medicine Platform (IGNITE) Program.

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