Aarhus University Seal / Aarhus Universitets segl

Surprising new mechanism for gene expression regulation

A new important role for a protein connected to the proper function of neurons has been discovered by a research group from MBG, Aarhus University. The studies shed new light on gene expression regulation and may ultimately lead to an understanding of how neurological defects occur when this protein is mutated.

2015.06.26 | Lisbeth Heilesen

Nuclear mRNA with a poly(A) tail is normally bound by Nab2, exported to the cytoplasm for translation into proteins and finally turned-over as shown on the left. In the absence of Nab2, the RNA is unprotected and degraded already in the nucleus by exoribonucleases Rrp6 and Dis3. Figure: Manfred Schmid.

The MBG researchers have studied a protein called Nab2, which is found in baker’s yeast. The human version of Nab2 – called ZC3H14 – is required for the proper function of neurons, and mutations in the ZC3H14 gene were recently linked to the inherited disease NS-ARID that causes intellectual disability in children. Studies from yeast therefore aim to shed light on the function of Nab2/ZC3H14 and ultimately how alterations in gene expression can lead to neurological defects.

Background

All living cells are small factories that constantly produce new proteins and recycle old ones. Information about the nature and the amount of proteins produced is encoded in a cell’s genome and decoded into proteins in a complex chain of events termed “gene expression”. The amount of proteins that needs to be produced by individual cells determines their identity and varies greatly between cell types and growth conditions. Strict control over the gene expression process is therefore of paramount importance for all life.

The present study has discovered a new regulatory principle for controlling gene expression that targets the so-called messenger RNA (mRNA). mRNAs are copies of individual genes that carry the genetic information from the genome to the site of protein synthesis. Control over the amount of mRNA determines how much protein can be produced for each gene in a cell and is therefore a key to regulate cellular metabolism.

The mRNA is a long linear molecule, which contains a specific tag at its rear end, the so-called poly(A) tail, and Nab2 binds to poly(A) tails of mRNAs. In the new study, an unexpected function of Nab2 was disclosed. Nab2 was previously believed to be required mostly for cellular transport of mRNA. In the new study, a novel method that allows for very rapid depletion of nuclear proteins was employed. This now shows that Nab2 is also critically required for mRNA production. Depletion of Nab2 leads to the untimely degradation of mRNA soon after its transcription in the cell nucleus and causes disappearance of most cellular mRNAs. Further investigations revealed that mRNAs are synthesized normally after Nab2 nuclear depletion, but instead degraded immediately after their production by luring RNA degrading enzymes. Hence, Nab2 is required to protect poly(A) tails of young mRNAs from premature decay as shown in the Figure below.

A second major insight from the study was that this phenotype is mostly observed immediately after Nab2 depletion. That is, cells can partially restore mRNA levels during long-term depletion, which also explains why previous studies failed to identify this function of the protein.

That mRNA critically requires protective measures to survive in the nucleus is a new concept that is likely exploited by the cell for gene expression regulation purposes. At the same time, recovery during long-term depletion implies that compensatory mechanisms are at play. This underscores the versatility of cell function, allowing to balance malfunctioning of single factors. Future efforts will now be devoted to explore in detail how cells compensate for Nab2 loss during long-term depletion and how Nab2 and nuclear decay factors impact gene expression regulation. This may reveal secrets about Nab2’s famous human cousin ZC3H14, ultimately leading to a better understanding of how neurological defects occur when this protein is mutated.


The Aarhus site of the research project was carried out by team leader Manfred Schmid together with PhD-student Pawel Olszewski from Torben Heick Jensen’s laboratory at the centre for mRNP Biogenesis and Metabolism, Department of Molecular Biology and Genetics.

The work, published online at Cell Reports: The Nuclear PolyA-Binding Protein Nab2p Is Essential for mRNA Production, was a joint collaboration with researchers at the European Molecular Biology Laboratories in Heidelberg.


Further information

Team leader Manfred Schmid (ms@mbg.au.dk) – cell +45 24474293 og

Centre leader, Professor Torben Heick Jensen (thj@mbg.au.dk), cell +45 60202705

both at the ’Centre for mRNP Biogenesis and Metabolism
Department of Molecular Biology and Genetics, Aarhus University, Denmark.

Research