MIT researchers have made a groundbreaking discovery in RNA splicing regulation, revealing a new layer of control that influences the expression of half of all human genes. This breakthrough has significant implications for our understanding of gene expression and its role in disease.
RNA splicing is a critical process that allows cells to control gene expression. A recent study by MIT Biologists has revealed a new layer of regulation in this process, which influences the expression of about half of all human genes.
RNA splicing is a critical process in gene expression where introns (non-coding regions) are removed and exons (coding regions) are joined together to form a mature messenger RNA (mRNA) molecule.
This process occurs in the nucleus and is essential for producing functional proteins from genetic information.
During splicing, small nuclear ribonucleoproteins (snRNPs) recognize and remove introns, while simultaneously joining exons together using a 5' to 3' phosphodiester bond.
RNA splicing is a complex process that ensures the accurate transmission of genetic information from DNA to protein.
The researchers discovered that a family of proteins called LUC7 plays a crucial role in determining which sites on the messenger RNA molecule the spliceosome will target. The spliceosome is a large protein-RNA complex that removes introns from mRNA and splices back together the coding regions, known as exons.
The Role of LUC7 Proteins in RNA Splicing
LUC7 proteins associate with U1 snRNA, which binds to the 5′ splice site at the beginning of the intron. The researchers found that two of the three human LUC7 proteins interact specifically with one type of 5′ splice site, called ‘right-handed,’ while a third protein interacts with a different type, known as ‘left-handed.’
About half of human introns contain a right- or left-handed site, while the other half do not appear to be controlled by interaction with LUC7 proteins. This type of control adds another layer of regulation that helps remove specific introns more efficiently.
RNA splicing is a crucial process that regulates gene expression by removing non-coding regions and joining coding exons.
This complex mechanism involves various factors, including the spliceosome, which is composed of five small nuclear ribonucleoproteins (snRNPs).
The splicing process can be regulated at multiple levels, including alternative splicing, where a single gene produces multiple proteins with distinct functions.
According to the Human Genome Project, approximately 95% of human genes undergo alternative splicing, highlighting its significance in genetic diversity and disease susceptibility.
Implications for Gene Regulation and Disease
The discovery of this new layer of regulation has significant implications for our understanding of gene expression and its role in disease. Previous work has shown that mutation or deletion of one of the LUC7 proteins is linked to blood cancers, including acute myeloid leukemia (AML). The researchers found that AMLs that lost a copy of the LUC7L2 gene have inefficient splicing of right-handed splice sites.
This knowledge could aid in the design of therapies that exploit these splicing differences to treat AML. Additionally, small molecule drugs for other diseases, such as spinal muscular atrophy, stabilize the interaction between U1 snRNA and specific 5′ splice sites. Understanding how LUC7 proteins influence these interactions could improve the specificity of this class of small molecules.
Evolutionary Conservation of RNA Splicing
The researchers also found that introns in plants have right- and left-handed 5′ splice sites that are regulated by Luc7 proteins. This suggests that this type of splicing arose in a common ancestor of plants, animals, and fungi, but was lost from fungi soon after they diverged from plants and animals.
Future Research Directions
The researchers now plan to further analyze the structures formed by the interactions of LUC7 proteins with mRNA and the rest of the spliceosome. This could help them figure out in more detail how different forms of Luc7 bind to different 5′ splice sites.
Acute myeloid leukemia (AML) treatment typically involves a combination of chemotherapy, radiation therapy, and/or stem cell transplantation.
Chemotherapy uses medications to kill cancer cells, while radiation therapy employs high-energy rays to destroy cancer cells.
Stem cell transplantation replaces damaged bone marrow with healthy stem cells.
Targeted therapies, such as venetoclax, are also used to treat specific AML subtypes.
Clinical trials may offer additional treatment options.
Treatment plans are tailored to individual patients based on age, overall health, and disease characteristics.
The research was funded by the U.S. National Institutes of Health and the German Research Foundation.
