A non-coding RNA gatekeeper of gene expression
An international team of scientists has uncovered new roles for a non-coding RNA in the control of gene expression in embryonic stem cells and other progenitor cells. This study is now published in the journal Genome Biology.
The researchers examined the control of gene expression in embryonic stem cells, which have the capacity to give rise to all cell types present in the adult body. Which cell type an embryonic stem cell develops into depends on which genes are expressed. The activity of RNA polymerases that read and transcribe the appropriate genes into RNA, are fundamental to this process.
Non-coding RNAs, which do not code for a protein, have emerged as important gene regulators. When the researchers studied the non-coding RNA 7SK, one of the first non-coding RNAs to be identified as well as being one of the most well characterized, they uncovered previously unnoticed functions. They found that this non-coding RNA acts as a gatekeeper of transcription in embryonic stem cells, preventing genes usually expressed in cells of the brain to be aberrantly expressed in these stem cells.
The team also found that this non-coding RNA unexpectedly controls other aspects of RNA polymerase II activity, which have remained incompletely understood despite intense research. First, it was uncovered that 7SK prevents the polymerase to go in the antisense direction, away from the gene start site. 7SK thereby controls the expression of non-coding RNAs located at bidirectional gene promoters, which can be read from both directions. In addition, 7SK assures that RNA polymerase II stops at the end of genes. Without a proper stop the expression of neighboring genes might be affected. In other words, 7SK not only regulates the expression of genes, it also helps to define their boundaries.
Also, 7SK might have similar regulatory roles in other cell types. These include neural stem cells and precursor cells that develop into oligodendrocytes, which protect nerves by wrapping them in insulating myelin.
"We are currently investigating the molecular mechanisms by which this non-coding RNA acts and whether it can modulate the differentiation capacity of these stem/progenitor cells", says first author Gonçalo Castelo-Branco, principal investigator at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet. Oligodendrocyte precursors can be important targets for cell-based therapies in demyelinating diseases such as multiple sclerosis."
The work is a collaboration of scientists at Karolinska Institutet and the Gurdon Institute and the European Bioinformatics Institute (EMBL), both at University of Cambridge in the United Kingdom. Dr. Gonçalo Castelo-Branco was previously in Professor Tony Kouzarides' research group at the Gurdon Institute. The work at Karolinska Institutet was funded by the Swedish Research Council.