Nouria Hernandez performed her thesis research on mRNA splicing with Dr. Walter Keller at the University of Heidelberg in Germany and received her PhD in 1983. She did her postdoctoral studies with Dr. Alan M. Weiner at Yale University in New Haven, Connecticut, USA, working on 3’ end formation of the U1 small nuclear RNA. She then joined Cold Spring Harbor Laboratory at Cold Spring Harbor, New York, in 1986 as an Assistant Professor. She became a Cold Spring Harbor Laboratory Professor in 1993 and joined the Howard Hughes Medical Institute as an Associate Investigator in 1994. She became a full Howard Hughes Medical Institute Investigator in 1999. In 2005, she joined the faculty of the UNIL as a Professor and as the Director of the Center for Integrative Genomics (CIG). From 2016 to 2021, she was Rector of the University of Lausanne.
Mechanisms of basal and regulated RNA polymerase II and III transcription of non coding RNA genes in mammalian cells
The task of transcribing the human genome is shared among three main RNA polymerases (Pol) known as Pol I, Pol II, and Pol III. Pol I transcribes the repeated 45S transcription unit, which gives rise to the 28S, 18S, and 5.8S ribosomal RNAs. Pol II transcribes the mRNA genes encoding proteins as well as most small nuclear RNA (snRNA) and microRNA genes. Thus, in contrast to Pol I, Pol II recognizes a large variety of promoter structures, reflecting the intricate regulation of its target genes in processes such as cell growth, proliferation, differentiation, and responses to various stresses. Pol III transcribes a collection of short genes giving rise to non-coding RNAs that are essential for cellular metabolism such as tRNAs and the ribosomal 5S RNA, as well as some regulatory RNAs such as, for example, some microRNAs or 7SK RNA. We study the mechanisms that govern transcription of Pol II snRNA genes as well as Pol III genes. Both classes of genes are relatively understudied compared to classical Pol II mRNA-encoding genes, yet their regulation is of great importance for cell metabolism. Our recent focus has been in understanding:
- mecanisms of selective Pol II and Pol III recruitment
- Pol III regulation
- the consequences of Pol III deregulation
Mechanism of selective recruitment of RNA polymerases II and III to snRNA gene promoters.
In collaboration with Dr. A. Vannini and his group, we set out to analyze and compare, step by step, the assembly of a Pol II and a Poll III transcription initiation complex on Pol II and Pol III snRNA promoters. Together with determination of crystal structures of various component of the Pol III transcription apparatus, this study provides a picture of how, very early in the assembly of the transcription initiation complex, the path to Pol II or Pol III recruitment is determined.
Regulation of Pol III genes
Unlike Pol II genes, which harbor a wide varity of promoter structures, Pol III genes have only three main types of promoters, called type 1, 2 and 3. Because of this structural simplicity, it has long been thought that Pol III promoters were basically all co-regulated. We have examined ths question both in cultured cells and in the mouse, in a variety of systems, for example in celles deprived of serum and then serum stimulated, or in the mouse during the diurnal cycle of after fasting and re-feeding. Most recently, we have examined how Pol III occupancy of Pol III genes varies during mouse liver regeneration, when liver cells exit the G0 phase and enter the cell cycle. The results reveal differential regulation of genes even with the same type of promoters: for example, all tRNA genes except for selenocysteine tRNA genes are type 2 genes, yet some of them are always silent, some of them are always expressed at very high levels, and another set adapts Pol III occupancy and transcription rates to changing conditions. The factors regulating these different genes include intrinsic promoter strength as well as chromatin environment and modifications. The genes that remain always active include all isoacceptors types, thus ensuring that translation can occur in all conditions.
The consequences of Pol III deregulation
We and others have characterized a repressor of Pol III transcription called Maf1, which acts by binding directly to Pol III. Mice lacking Maf1 are lean and resistant to a high fat diet as a result of metabolic inefficiency. Increased energy expenditure results at least in part from a futile cycle of tRNA synthesis and degradation stemming from the deregulation of Pol III activity, which reprograms metabolism to meet the increased demand in nucleotides. Moreover, these mice display slightly reduced translation in the liver. To further our understanding of this phenotype, we are examining a mouse lacking Maf1 specifically in the liver.
Yeganeh, M., and Hernandez, N. (2020). RNA polymerase III transcription as a disease factor. Genes Dev. 34, 865-882. URL
Bonhoure, N., Praz, V., Moir, R.D., Willemin, G., Mange, F., Moret, C., Willis, I.M., and Hernandez, N. (2020). MAF1 is a chronic repressor of RNA polymerase III transcription in the mouse. Sci Rep. 10, no 11956. URL
Dergai, O., and Hernandez, N. (2019). How to recruit the correct RNA Polymerase? Lessons from snRNA genes (2019). Trends Genet. 35, 457-469. URL
Yeganeh, M., Praz, V., Carmeli, C., Villeneuve, D., Rib, L., Guex, N., Herr, W., Delorenzi, M., Hernandez, N., and the CycliX consortium (2019). Differential regulation of RNA polymerase III genes during liver regeneration. Nucleic Acids Res. 47, 1786-1796. URL
Dergai, O., Cousin, P., Gouge, J., Satia, K., Praz, V., Kuhlman, T., Lhôte, P, Vannini, A., Hernandez, N. (2018). Mechanism of selective recruitment of RNA polymerases II and III to snRNA gene promoters. Genes Dev. 32, 711-722. URL
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