Introduction:
UCLA researchers in the Department of Biological Chemistry have discovered a novel mechanism to address how X-chromosome inactivation happens. Targeting specific protein-protein interactions in this biological pathway may promote reactivation of X-chromosome to treat X-linked diseases.
Background:
Sex differences in human disease are often attributed to sex hormones that influence the function of susceptible genes. However, a major cause of disease expression derives itself from the sex chromosome, originating in how males and females transcribe the gene-rich human X chromosome. The X chromosome carries 867 known protein-coding genes and various genes encoding long-non-coding RNAs. When pathogenic variants arise in these gene rich chromosomes, they can lead to lethal consequences.
Females carry two copies of the X chromosome, and the double dose of most X-linked genes is incompatible with development. To correct this imbalance, mammalian females have evolved a unique mechanism called X-chromosome inactivation (XCI), i.e., transcriptionally silencing most of the genes on one of their two X-chromosomes. Mechanistically, the process of XCI remains elusive; yet it is well established that the long-noncoding RNA Xist mediates XCI. Understanding the underlying mechanism of XCI is critical to the development of novel gene therapy approaches for X-linked diseases.
Many X-linked genes are involved in the development of diseases. As an example, several neurodevelopmental disorders in females are caused by heterozygous mutations of genes on the X chromosome, including Rett Syndrome, which is causally linked to mutations in the X-linked gene MECP2. In females with Rett Syndrome, the inactive X chromosome serves as a reservoir for the functional gene copy that could replace the expression of a disease allele from the active X chromosome. Animal studies have shown that simply reactivating or delivering this functional gene copy of MECP2 – even after disease symptoms emerge – can lead to complete reversion of neurological defects. Thus, the reactivation of the inactive X chromosome could be a key strategy for treating X-linked diseases such as Rett Syndrome. However, the major gap in applying this strategy in patients has been the lack of knowledge of how the long noncoding RNA Xist inactivates the X chromosome and the mechanisms that would lead to its reactivation.
Innovation:
Dr. Kathrin Plath and colleagues in the Department of Biological Chemistry at UCLA have discovered a novel mechanism to explain how X-chromosome inactivation happens. They used super resolution microscopy and detailed analysis to show how long noncoding RNA Xist (X-inactive specific transcript) guides proteins into its compartment and how this leads to a specific effect on gene expression. Their results suggest that Xist RNA can attract RNA-binding proteins mediating their macromolecular crowding via protein-protein interactions and that these protein-protein interactions are critical for gene silencing. Inhibition of these interactions may promote reactivation of X-chromosome and brings hope to cure some X-linked diseases.
Applications:
Advantages:
State of Development: The mechanism of how lncRNA Xist mediates X-chromosome inactivation was discovered. Currently, a series of inhibitors to block specific protein-protein interactions to promote reactivation of the inactive X chromosome are being surveyed.
Related Papers (from the inventors only)
Xist nucleates local protein gradients to propagate silencing across the X chromosome. Yolanda Markaki, Johnny Gan Chong, Christy Luong, Jessie Wang, Elsie Jacobson, Davide Maestrini, Bhaven Mistry, Shawn Tan, Iris Dror, Abhik Banerjee, Johannes Schoenenberg, Mitchell Guttman, Tom Chou, Kathrin Plath (Manuscript in in revision)