Schraga Schwartz & Gil Ast Discuss the Precision of RNA Splicing

New Hot Paper Commentary, January 2011

Schraga Schwartz & Gil Ast

Article: Chromatin organization marks exon-intron structure

Authors: Schwartz, S;Meshorer, E;Ast, G
Volume: 16, Issue: 9, Page: 990-U117, Year: SEP 2009
* Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, Ramat Aviv, Israel.
* Tel Aviv Univ, Sackler Fac Med, Dept Human Mol Genet & Biochem, Ramat Aviv, Israel.
* Hebrew Univ Jerusalem, Dept Genet, Alexander Silberman Inst Life Sci, IL-91904 Jerusalem, Israel.

Schraga Schwartz & Gil Ast talk with and answer a few questions about this month's New Hot Paper in the field of Biology & Biochemistry.

SW: Why do you think your paper is highly cited?

Our paper identified a potential link between two fundamental molecular layers of gene regulation: chromatin structure and the architecture of exons and introns. RNA splicing—the process in which introns are removed and exons are ligated to each other to form mature RNA molecules—and chromatin structure both play decisive roles in most, if not all, fundamental processes occurring across all eukaryotic cells, from yeast to human and disruptions in either can result in disease. Therefore these two fields have been actively but mostly independently studied over many years.

Our manuscript suggests that in fact these two processes are linked: the precision of RNA splicing may be determined by chromatin structure. This opens up a new way of thinking about these processes, what regulates them, and what may be going wrong in cases in which they are disrupted.

SW: Does it describe a new discovery, methodology, or synthesis of knowledge?

Coauthor Gil Ast
"Coauthor Gil Ast."

The paper is based on a synthesis of knowledge that led to a new discovery. Several datasets had become available mapping nucleosome positioning at a genome-wide level. In parallel, the positions of exons and introns across the human genome were available. By integrating these two available resources, we were able to make our discovery.

SW: Would you summarize the significance of your paper in layman's terms?

For years researchers have tried to determine how cells precisely identify short sequences, termed exons, from within overwhelming long stretches of sequence that do not code for protein, termed introns, in order to correctly make messenger RNA molecules. Cells must accurately remove introns and ligate exons to yield the mature mRNA product, which serves as a molecular blueprint for creating proteins.

What we discovered in our work was that one potential source controlling this process lies in the DNA sequence that serves as a template for the mRNA. More specifically, we found that the way in which genomic DNA is bound by protein complexes called nucleosomes differs along exonic and intronic sequences. Thus, these differences at the DNA level might determine the subsequent differentiation between the two at the RNA level.

Our results suggest that perhaps, in trying to understand how splicing is brought about, researchers should focus not only on the RNA, as they have traditionally done, but also on the chromatin structure. Since aberrant splicing is implicated in various diseases, this suggests a new direction for studies aimed at understanding the molecular pathways leading to these diseases.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

"Our paper identified a potential link between two fundamental molecular layers of gene regulation: chromatin structure and the architecture of exons and introns."

Our lab has been trying to understand the remarkable ability of the splicing machinery to precisely recognize exons for a decade now. Over the past several years various hints from different laboratories have emerged that chromatin might be part of this story. During this period, sequencing technology has undergone a considerable boost, allowing the profiling of chromatin structure at a genome-wide level. Thus, our work stands on the shoulders of years of efforts in the chromatin and splicing fields and on technological advances, allowing us to directly assess the link between the two.

SW: Where do you see your research leading in the future?

The fact that DNA structure, which is epigenetically determined, may be linked with splicing opens up numerous directions for the future. First, it must be experimentally verified whether chromatin and splicing are linked. Second, the biological mechanism that links the two processes must be elucidated.

More generally, however, if it proves true that one epigenetic factor influences splicing, this opens up the possibility that other epigenetic factors, such as DNA methylation, impact splicing as well. Indeed, various works published over the last year have established that the DNA encoding exons differs from introns in this respect as well. How these different epigenetic factors act and interact to allow precise splicing and dynamically regulate it are key questions we will be working on.

SW: Do you foresee any social or political implications for your research?

One potential implication of our work, of which we are yet remote at this early stage, is in the field of therapeutics. Aberrant splicing is known to be involved in a large number of diseases, including cystic fibrosis, familial dysautonomia, and various cancers as well. To understand why splicing is not occurring as it should in these diseases, it is necessary to understand the basic principles governing splicing.

If it can be established that in some of these diseases the cause of the aberrant splicing, leading to the disease, is in disrupted chromatin structure, then this will be the first step towards developing a therapy that aims to restore the intact chromatin structure, which in turn will restore the normal splicing pattern.End

Gil Ast
Department of Human Molecular Genetics & Biochemistry
Sackler Medical School
Tel Aviv University
Tel Aviv, Israel

Schraga Schwartz
Department of Molecular Genetics
Weizmann Institute of Science
Rehovot, Israel



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