Research

Our current research has three main focus areas:

  1. Regulation of metabolic homeostasis though sugar sensing
  2. New regulators of nutrient-dependent growth control
  3. Nutrient-induced responses in tissue stem cell regulation

Our lab is multidisciplinary, international and collegial and we are committed to offer high-standard scientific training in a supportive environment. If you wish to join our lab or collaborate, do not hesitate to contact: ville.hietakangas@helsinki.fi

Regulation of metabolic homeostasis through sugar sensing

Sugars are highly energetic macronutrients and an essential part of diet for many animals. Excessive consumption of dietary sugars has been associated with increased risk for metabolic diseases in human. However, the genetic determinants that define the range of tolerated sugar intake and the individual's risk for metabolic disturbance on high sugar diet are poorly understood. We aim to understand how cellular signaling and gene expression is regulated in response to dietary sugars and how these genetic responses influence animal physiology.

Our recent work has focused on the physiological role of Mondo (ChREBP) –Mlx, which is a transcription factor complex mediating intracellular sensing of sugar metabolites. We have discovered that loss of Mondo-Mlx leads to striking sugar intolerance in Drosophila, which suggests that these transcription factors and their targets may be relevant in adjusting the limits of safe sugar utilization (Havula et al., 2013). Mondo-Mlx is a master regulator of a sugar-sensing gene regulatory network, including other transcription factors, such as Cabut (Klf10) and Sugarbabe (GLIS2) (Bartok et al., 2015; Mattila et al., 2015) (Figure 1). Mondo-Mlx is also interconnected with hormonal signaling, as it regulates the sugar-inducible expression of TGF-beta/Activin ligand Dawdle (Mattila et al., 2015). Consequently, Mondo-Mlx is contributes to the regulation of the majority of sugar-regulated genes in Drosophila tissues, including genes involved in nutrient transport as well as lipid and amino acid metabolism (Mattila et al., 2015). Genomic variants of human Mondo ortholog ChREBP (MLXIPL) associate strongly with circulating triglyceride levels, which is a cardiometabolic risk factor. The homologs of Drosophila Mondo-Mlx targets are significantly enriched among genes that are in the vicinity of other triglyceride-associated SNPs (Mattila et al., 2015), which highlights the conservation of intracellular sugar sensing in animals. Our current work focuses on new members of the Mondo-Mlx-dependent gene regulatory network, as well as other sugar sensing mechanisms that act in parallel to Mondo-Mlx. We are also exploring whether the mechanisms we have discovered contribute to pathophysiologies in human.

Figure 1. Mondo-Mlx is a master regulator of a sugar-sensing regulatory network, including transcription factors Cabut and Sugarbabe as well as TGF-beta/Activin ligand Dawdle.

In addition to metabolic pathway activities, redox balance needs to be closely controlled in response to diet. Redox balance in maintained by Nicotinamide cofactors NAD(H) and NADP(H), which contribute to metabolic reactions, ATP production and counteracting oxidative stress. Our recent work has shown that a key regulator of NADPH redox balance is protein kinase SIK3, which is a transcriptional target of Mondo-Mlx (Teesalu et al., 2017). SIK3 phosphorylates the rate-limiting enzyme of the pentose-phosphate pathway, which promotes reduction of NADP+ (Figure 2). Loss of SIK3 leads to oxidative stress on high sugar diet and loss of sugar tolerance. SIK3 converges with Mondo-Mlx to maintain sugar tolerance, as Mondo-Mlx promotes the pentose phosphate pathway transcriptionally (Mattila et al., 2015). Thus, our work has uncovered dynamic regulation of NADP(H) redox balance as a key mechanism to sustain sugar tolerance in changing nutrient landscape. Our current work focuses on understanding the role of redox-sensitive gene regulation in the control of metabolic homeostasis in response to sugars.

Figure 2. SIK3 and Mondo-Mlx synergize to control the pentose phosphate pathway, which maintains redox balance upon sugar feeding.

New regulators of nutrient-dependent growth control

In multicellular animals, growth rate needs to be balanced in all tissues, which sets the requirement for systemic hormonal control. A key hormonal mechanism regulating growth in response to nutrition is the insulin-like pathway, which in flies is activated by insulin-like peptides and in vertebrates by insulin-like growth factors. We have used the power of Drosophila genetics to screen for new genes that control the secretion of insulin-like peptides (ILPs) in response to nutrition. These efforts led to the finding that an atypical MAP kinase ERK7 (also known as ERK8 and MAPK15) is a potent inhibitor of ILP secretion during nutrient starvation (Hasygar & Hietakangas, 2014). Consequently, ERK7 activity in the insulin producing cells inhibits animal growth. ERK7 expression is activated by starvation as well as in conditions of inhibited ribosome biogenesis. Our current work is addressing the role of ERK7 in nutrient-dependent regulation of growth and metabolism in other metabolically-relevant tissues.   

It is well-established that nutrient-dependent growth control is coordinated by the Insulin/mTOR pathway. This pathway integrates information from hormonal signals as well as intracellular amino acid and energy levels to control anabolic reactions of the cell. A rate limiting process for cell growth is ribosome biogenesis. How ribosome biogenesis is regulated by mTOR complex 1 (mTORC1) and other growth-promoting pathways has remained insufficiently understood. We have discovered a new regulator involved in nutrient-dependent ribosome biogenesis, called PWP1 (Liu et al., 2017). PWP1 is a chromatin-binding protein conserved in eukaryotes, which promotes nutrient-responsive ribosomal RNA (rRNA) expression by RNA polymerase (Pol) I and III (Liu et al., 2017; Liu et al., 2018). Drosophila mutants lacking PWP1 show impaired growth, which is consistent with its role as a driver of ribosomal RNA expression. PWP1 is regulated at the levels of gene expression by the transcription factor Myc, which acts downstream of mTORC1 signaling. PWP1 is also phosphorylated in mTORC1-dependent manner and the PWP1 phosphorylation is needed for its localization in the nucleolus, the site of Pol I activity. Thus, PWP1 is a nutrient-responsive regulator of rRNA expression. Our current work focuses on the role of PWP1 in growth and metabolic control beyond the ribosome biogenesis.

Cancer cells depend on high protein biosynthetic activity and display highly elevated ribosome biogenesis. We have observed that PWP1 expression in elevated in human head and neck squamous cell carcinoma (HNSCC) tumours and the expression level of PWP1 positively correlates with the aggressiveness of the tumor (Liu et al., 2017). Knockdown of PWP1 in HNSCC tumour cells inhibits proliferation, demonstrating the functional importance of PWP1. Future studies will be needed to address the importance of PWP1 in a broader spectrum of cancer types.

Nutrient regulation of tissue stem cells

Stem cells renew our tissues, and they must be carefully controlled to secure tissue homeostasis. For example, the intestinal epithelium undergoes constant turnover, which depends on the regulation of intestinal stem cell (ISC) proliferation and differentiation. Earlier studies have shown that Drosophila ISCs are a genetically tractable model to study the mechanisms that control tissue stem cells in vivo. Moreover, the ISCs respond to nutrient-induced cues, making this system an optimal model to address gene-nutrient interactions in stem cell control. On one hand, stem cells need to robustly sustain a metabolic profile that supports the stem cell identity. On the other hand, stem cells need to integrate nutrient-derived signals to dynamically control the cell cycle, self-renewal, and differentiation in order to match tissue function and repair with nutrient availability. Understanding stem cell specific metabolism and nutrient sensing may therefore provide new means to manipulate stem cell function, which can benefit the development of new therapies in longer perspective.

Our ongoing work on intestinal stem cells relies on genetic control of intestinal cell types, use of controlled dietary schemes to influence nutrient availability as well as cell imaging, transcriptomics and metabolomics.  Through the close collaboration within the Center of Excellence in Stem Cell Metabolism (MetaStem) we will be able to test the conservation of our findings using mammalian stem cell models. Within MetaStem, we are also setting up a metabolomics platform, specifically designed for high sensitivity to allow analysis of metabolites from challenging stem cell and tissue samples.