We bridge computational and experimental sciences to understand the impact of the non-coding genome and sex chromosomes on disease.
Uncovering the missing X factors and their function to understand sex bias in heart disease
Cardiovascular disease (CVD) occurs and progresses differently in men and women, with men developing the disease earlier in life and the risk of disease increasing dramatically with age in both sexes. Many biological factors contribute to sex differences, beginning at the time of conception. Hormonal differences have been suggested to account for the sex difference by the observation that younger women are routinely protected from CVD until postmenopause. Other likely contributors to sex differences are genes that escape female X chromosome inactivation, an understudied epigenetic phenomenon that has not been linked to sex differences in heart disease. These so-called escape genes are twice as abundant in females as in males and are therefore, likely to contribute to sex differences. We will combine allele-specific multi-omics approaches with genetic and disease models to deepen our understanding of the molecular mechanisms underlying sex bias in CVD and to develop RNA-based therapies for sex-specific treatment.
Linking disease and age-specific epigenetic changes to dysregulation of imprinted genes
Long non-coding RNAs (lncRNAs), a heterogeneous group of RNAs longer than 200 nucleotides with limited coding potential, are usually lowly expressed, highly tissue-specific, and can act as transcriptional regulators of the genome. Although many lncRNAs have been identified, their mechanism of action remains mostly unknown.
The first functional lncRNAs have been discovered for two epigenetic processes, genomic imprinting and X-chromosome inactivation (XCI). Interestingly, imprinted lncRNAs have recently been implicated in many cardiovascular diseases. Given that imprinted lncRNAs are epigenetically controlled, one question is whether age- and disease-related epigenetic changes lead to lncRNA dysregulation and consequently to changes in the levels of their targets. Here, we use allele-specific genomics to investigate whether heart disease is a consequence of age- and/or disease-specific epigenetic changes in imprinted loci that result in gene dosage imbalances in these regions.
Decoding the non-coding genome, one allele at a time
Only about one percent of DNA consists of protein-coding genes, while the rest is non-coding. These non-coding regions contain sequences that act as regulatory elements, such as promoters and enhancers, or as non-coding RNAs, both of which help determine when and where genes are turned on or off. Over the past few decades, regulatory regions have been extensively mapped across tissues and development, and genome-wide association studies (GWAS) have led to the identification of a comprehensive catalog of human genetic disease variants. However, for most non-coding regulatory regions, the affected target genes and mechanisms of action are unknown.
Here, we aim to use our unique allele-specific genomics expertise to link regulatory regions such as lncRNAs or enhancers to their target genes and subsequently to their mechanisms of action. By integrating the identified linkages with non-coding GWAS variants, we aim to link a large proportion of the 93% of non-coding disease variants to their corresponding target genes.
In vivo screening for CVDs relevant lncRNAs
Genetically engineered in vivo models are essential to reveal functional lncRNAs and to dissect down to the functional domain. The CRISPR revolution has brought several paradigm shifts for embryo manipulation. Specifically, CRISPR greatly facilitates the ability to create knockout, knock-in, and large deletion rapidly. Recently a new method termed GONAD was developed, which uses electroporation of the oviduct from pregnant females, carrying Zygotes together with the injected CRISPR editing mix to deliver the editing mix in situ. We will take advantage of the GONAD approach to systematically screen for functional lncRNA in the cardiovascular system in vivo and further identify their mechanism of action.
