Felix Naef | EPFL Graph Search

Felix Naef studied theoretical physics at the ETHZ and obtained his PhD from the EPFL in 2000. He then received postdoctoral training at the Center for Studies in Physics and Biology at the Rockefeller University (NYC) under the guidance of Prof. Magnasco. His research focuses on the modeling and interpretation of high-throughput functional data and the study of biomolecular oscillators. He joined ISREC as an associate scientist in early 2004 and is currently Associate Professor in the Institute of Bioengineering (IBI).

Sex-dimorphic and age-dependent organization of 24-hour gene expression rhythms in humans

Cédric Gobet, Felix Naef, Lorenzo Talamanca

The circadian clock modulates human physiology. However, the organization of tissue-specific gene expression rhythms and how these depend on age and sex is not defined in humans. We combined data from the Genotype-Tissue Expression (GTEx) project with an algorithm that assigns circadian phases to 914 donors, by integrating temporal information from multiple tissues in each individual, to identify messenger RNA (mRNA) rhythms in 46 tissues. Clock transcripts showed conserved timing relationships and tight synchrony across the body. mRNA rhythms varied in breadth, covering global and tissue-specific functions, including metabolic pathways and systemic responses. The clock structure was conserved across sexes and age groups. However, overall gene expression rhythms were highly sex-dimorphic and more sustained in females. Rhythmic programs generally dampened with age across the body.

AMER ASSOC ADVANCEMENT SCIENCE2023

Spatiotemporal Metabolic Liver Zonation and Consequences on Pathophysiology

Felix Naef

Hepatocytes are the main workers in the hepatic factory, managing metabolism of nutrients and xenobiotics, production and recycling of proteins, and glucose and lipid homeostasis. Division of labor between hepatocytes is critical to coordinate complex complementary or opposing multistep processes, similar to distributed tasks at an assembly line. This so-called metabolic zonation has both spatial and temporal components. Spatial distribution of metabolic function in hepatocytes of different lobular zones is necessary to perform complex sequential multistep metabolic processes and to assign metabolic tasks to the right environment. Moreover, temporal control of metabolic processes is critical to align required metabolic processes to the feeding and fasting cycles. Disruption of this complex spatiotemporal hepatic organization impairs key metabolic processes with both local and systemic consequences. Many metabolic diseases, such as nonalcoholic steatohepatitis and diabetes, are associated with impaired metabolic liver zonation. Recent technological advances shed new light on the spatiotemporal gene expression networks controlling liver function and how their deregulation may be involved in a large variety of diseases. We summarize the current knowledge about spatiotemporal metabolic liver zonation and consequences on liver pathobiology.

ANNUAL REVIEWS2023

Comprehensive analysis of the circadian nuclear and cytoplasmic transcriptome in mouse liver

Cédric Gobet, Clémence Yumie Syloun Hurni, Felix Naef, Benjamin Dieter Weger

In eukaryotes, RNA is synthesised in the nucleus, spliced, and exported to the cytoplasm where it is translated and finally degraded. Any of these steps could be subject to temporal regulation during the circadian cycle, resulting in daily fluctuations of RNA accumulation and affecting the distribution of transcripts in different subcellular compartments. Our study analysed the nuclear and cytoplasmic, poly(A) and total transcriptomes of mouse livers collected over the course of a day. These data provide a genome-wide temporal inventory of enrichment in subcellular RNA, and revealed specific signatures of splicing, nuclear export and cytoplasmic mRNA stability related to transcript and gene lengths. Combined with a mathematical model describing rhythmic RNA profiles, we could test the rhythmicity of export rates and cytoplasmic degradation rates of approximately 1400 genes. With nuclear export times usually much shorter than cytoplasmic half-lives, we found that nuclear export contributes to the modulation and generation of rhythmic profiles of 10% of the cycling nuclear mRNAs. This study contributes to a better understanding of the dynamic regulation of the transcriptome during the day-night cycle. Author summary Why was this study done? The circadian clock coordinates temporal gene expression programs to synchronise cellular and physiological functions with environmental time.The circadian clock impinges on many layers of gene regulation, from transcription to mRNA degradation in the cytoplasm.Specifically, whether temporal modulation of nuclear export could influence rhythmic mRNA expression was not known. What did the researchers do and find? We sequenced RNA from nuclear and cytoplasmic fractions from mouse livers sampled at different times of the day.Using a mathematical model describing temporal accumulation profiles of pre-mRNA, nuclear mRNA and cytoplasmic mRNA, we could estimate the nuclear export rates and cytoplasmic degradation rates of approximately 1400 genes.We observed rhythmic patterns in the nucleus that most likely originate from a rhythmic regulation of the nuclear export rate, affecting approximately 10% of the oscillations of the nuclear transcriptome in the liver. What do these findings mean? Our fractionated RNA analysis contributes to a better understanding of the dynamic regulation of the transcriptome during the daily cycle.The majority of the RNA transcripts are exported to the cytoplasm in less than 30 minutes, however, some are retained in the nucleus for several hours. Thus, cellular fractionation allows a finer resolution of temporal profiles in the different subcellular compartment, which is otherwise masked at bulk-level.

PUBLIC LIBRARY SCIENCE2022

Comprehensive analysis of the circadian nuclear and cytoplasmic transcriptome in mouse liver

Cédric Gobet, Clémence Yumie Syloun Hurni, Felix Naef, Benjamin Dieter Weger

PUBLIC LIBRARY SCIENCE2022