Ina Huppertz

Max Planck Institute for Biology of Ageing

RNA-binding Proteins in Metabolism and Ageing

In the Huppertz group, we work at the interface of ageing, metabolism, RNA and stem cell biology combining well-established molecular biology-based and biochemical assays with high-throughput screens.

Research Focus

The fine-tuning of metabolic processes is required for the self-renewal, proliferation and differentiation of a stem cell, which in turn affects its regenerative capacity. Perturbations in this metabolic balance can contribute to ageing and age-related pathologies, which can affect the quality of life of an individual, particularly when associated with cognitive decline.

In the Huppertz group, we are investigating the role of RNA-binding proteins (RBPs) in the metabolic rewiring of differentiating stem cells and during ageing. RBPs are a versatile group of proteins that can facilitate short- and long-term metabolic adjustments of cells undergoing cell division and differentiation (Esparza-Molto and Cuezva, 2020). In addition, RBPs can integrate metabolic stimuli through post-translational modifications (Choudhary et al., 2014), changes in localisation (Tischbein et al, 2019) or metabolite availability (PMID: 36608661). In recent years, several examples of canonical RBPs have emerged as regulators of energy metabolism during differentiation and ageing.

One example of a canonical RBP that affects the metabolic setup of the cell is YBX3. By binding to the 3' untranslated region, YBX3 stabilises the transcript of the amino acid transporter SLC7A5, indirectly altering the availability of large, neutral amino acids in the cell (Cooke et al, 2019). In addition, many essential metabolic enzymes have been identified that bind RNA in different cell types and organisms. Two simple types of RNA-enzyme interactions can be envisaged. On the one hand, metabolic enzymes could moonlight as RBPs and regulate the fate of their target RNAs. On the other hand, RNA could regulate these enzymes, a process we have recently described for the glycolytic enzyme enolase (Huppertz et al, 2022; Figure 1). This very large class of non-canonical RBPs could represent a new level of metabolic regulation.

“Science is magic that works.” – Kurt Vonnegut

Our Goals

We aim to understand how widespread and generalisable these novel roles of RBPs are and to disentangle the links between RNA and stem cell biology, metabolism and ageing.

We will use the metabolically dynamic system of mouse embryonic stem cells and their spontaneous differentiation, as well as induced pluripotent stem cells and neuronal and cardiomyocyte differentiation, to elucidate the involvement of canonical and non-canonical RBPs in their metabolic rewiring.

  • While the heterogeneity of stem cells, particularly neural stem cells, has been extensively studied with the advent of single-cell sequencing, assessing metabolite levels on a single-cell basis will provide new insights. To this end, we are developing a pipeline for metabolism-centric classification of our cells using genetically encoded metabolite sensors (as in Harada et al, 2020, Hung and Yellen, 2014 and Zhao et al, 2020; Figure 2), which can be combined with CRISPR/Cas9 screens targeting RBPs and RNA interactome capture (Perez-Perri et al, 2018). This will help us to identify the key RNA-binding players that contribute to the metabolic rewiring of differentiating stem cells.

Our overall goals are to investigate what regulates the metabolic changes that stem cells undergo during differentiation and ageing, what role metabolism plays in the ageing process of stem cells, and what coordinates cytosolic and mitochondrial metabolic pathways in ageing stem cells.

Key Publications

  1. Huppertz I, Perez-Perri JI, Mantas P, Sekaran T, Schwarzl T, Russo F, Ferring-Appel D, Koskova Z, Dimitrova-Paternoga L, Kafkia E, Hennig J, Neveu PA, Patil K, Hentze MW (2022). Riboregulation of Enolase 1 activity controls glycolysis and embryonic stem cell differentiation. Molecular Cell DOI: 10.1016/j.molcel.2022.05.019
  2. Perez-Perri JI, Ferring-Appel D; Huppertz I, Schwarzl T, Sahadevan S, Stein F, Rettel M, Galy B, Hentze MW (2023) The RNA-binding protein landscapes differ between mammalian organs and cultured cells. Nature Communications DOI: 10.1038/s41467-023-37494-w
  3. Cooke A, Schwarzl T*, Huppertz I*,#, Kramer G, Mantas P, Alleaume AM, Huber W, Krijgsveld J, Hentze MW# (2019) The RNA-Binding Protein YBX3 controls amino acid Levels by Regulating SLC mRNA Abundance. Cell Reports DOI: 10.1016/j.celrep.2019.05.039
  4. Haberman N*, Huppertz I*, Attig J, König J, Wang Z, Hauer C, Hentze MW, Kulozik AE, Le Hir H, Curk T, Sibley CR, Zarnack K, Ule J (2017) Insights into the Design and Interpretation of iCLIP Experiments. Genome Biology DOI: 10.1186/s13059-016-1130-x
  5. Huppertz, I., Attig, J., D’Ambrogio, A., Easton, L.E., Sibley, C.R., Sugimoto, Y., Tajnik, M., König, J., Ule, J. iCLIP: Protein–RNA Interactions at Nucleotide Resolution. Methods 65, 274–287 (2014).