Laboratory for Dynamic gene regulation

Background

Recent research has unraveled a remarkable diversity of chemical modifications that modify the coding properties of bases in DNA and RNA and the amino acids of a protein. Our aim is to identify writers, readers and erasers of such marks and to gain understanding of their biological relevance.

We are particularly interested in reprogramming of the human genome in meiosis and the preimplantation embryo. Moreover, novel mechanisms for gene-regulation might be crucial for understanding cancer development. Our current studies also include several novel models for post translational modifications in RNA. The reversible nature of some chemical modifications of RNA is a very recent discovery. Most of our studies rely on novel mutants in various model organisms. We collaborate with excellent national groups and also research groups in China, Holland, UK and USA. Our research group, and our Institute, is truly international with 70% international PhD students and post doctoral fellows. These include group members from Spain, Sweden, Germany, Ethiopia, UK, USA, China and France.


Challenges:


A broad repertoire of modifications is known to underlie adaptable coding and structural function of proteins, DNA and various RNA species. Methylations of mammalian DNA and histone residues are known to regulate transcription and the discoveries of demethylases that remove methylation in DNA and histones provide a basis for the understanding of dynamic regulation of mammalian gene expression. The reversions of methyl marks on DNA and proteins have been extensively studied the last decade. On the contrary, reversal of N6-methyladenosine (m6A) to adenosine (A) in messenger RNA (mRNA) was only identified recently (for the obesity risk gene, FTO). 6-methyladenine (m6A) is the most abundant internal base modification of messenger RNA (mRNA) in higher eukaryotes. We have identified a second m6A demethylase for mRNA (Zheng et al., Molecular Cell). Internal m6A is the most common modification of mRNA in higher eukaryotes. Male mice lacking Alkbh5 have elevated m6A levels in total mRNA and are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. The discovery of this RNA demethylase strongly suggests that the reversible m6A modification has fundamental and broad functions in mammalian cells and in human disease.


Projects:


• Identify molecular mechanisms underlying coding properties of methylated adenines in mRNA
• Understand meiotic failure in mice lacking mRNA demethylases
• Investigate gene-regulation in the maturation of sperm and egg, including meiosis
• Study genome regulation in the maternal to zygotic transition
• Stem cell biology


beskrivelse

ALKBH5 Catalyzes Demethylation of m6A-Containing ssRNA