Cell and Organelle Size Control
Schmoller LabAbout our Research
We study the impact of cell size on cell function and investigate how cells coordinate growth and division to control their size.
The human body consists of around 40 trillion individual cells. Each of them is a structurally distinct, (largely) independent, and self-sustaining unit. The size of a cell is a fundamental property, which is tightly controlled for each cell but can vary dramatically between cell types, and depend on external or internal cues. In recent years, cell size emerged as a major factor controlling cell function. For example, cell growth and biosynthetic processes, including protein production, are tightly linked to cell size. In addition, the size of subcellular organelles is well-defined and adjusted according to the overall cell size. Finally, cell size can play a regulatory role during specific biological processes such as early embryonic development. Given its central role in cell function, it may not be surprising that diseases such as cancer as well as aging often go along with a misregulation of cell size. Thus, understanding how cells regulate their size and the molecular processes through which cell size governs cell function is of paramount importance to capture the complexity of disease emergence and guide diagnostics and therapeutic approaches.
Many of the fundamental processes through which cell size impacts cell function are broadly conserved across eukaryotes. To address these questions, we, therefore, use two powerful and evolutionary distant model organisms: The budding yeast S. cerevisiae and the green alga C. reinhardtii. Besides the obvious advantages of these simple and well-characterized models, we can control the size of both organisms. Building on our previous work, we can genetically tune budding yeast cell size by controlled expression of physiological cell size regulators. For C. reinhardtii, we can employ its diurnal growth cycle to control the size with light and nutrients.
Using an interdisciplinary approach that combines quantitative biology, live-cell microscopy and AI-based image analysis, as well as mathematical modelling, we aim to identify conserved regulatory principles that will then guide our understanding of cell size in the context of human cells and diseases.
Each cell in an organism has to control its size by balancing cell growth, division, and cell death. In particular, proliferating cells coordinate cell division with cell size and growth. In yeast as well as in humans, this coordination occurs in part at the G1/S transition: Cells that are smaller at their birth grow more before they divide compared to cells that are born bigger. Not surprisingly then, cancer cells – which lost the regulation of growth and division – often have altered and more variable sizes compared to healthy cells. Using live-cell time-lapse imaging combined with yeast genetics and molecular biology, we aim to understand the molecular processes through which cells can sense their own size, and adapt their size upon environmental changes such as changing nutrient conditions.
Relevant publications:
- Schmoller et al., Nature, 2015
- Chandler-Brown et al., Curr. Biol., 2017
- Schmoller, Curr. Opin. Cell Biol., 2017
- Swaffer et al., Mol. Cell, 2021
- Schmoller et al., MBoC, 2022
People: Yagya, Benedikt
For most proteins, the synthesis rate increases in direct proportion to the cell volume because also the limiting machinery for transcription and translation, including RNA polymerase and ribosomes, increases in abundance as cells get bigger. This means that more proteins are produced when the cell grows bigger and thereby, stable protein concentrations can be maintained. However, histone proteins, which bind to the DNA to pack it into the nucleus, this machinery-limited regulation is not appropriate, because rather than constant concentrations, the cell needs histone amounts that are proportional to the DNA content.
If too many histone proteins are produced but the DNA amount stays the same, the DNA gets more compacted, and highly condensed DNA forms an obstacle for many cellular processes. In contrast, too few histones would lead to loosely packed DNA that can be processed without any control. Both scenarios would harm the integrity and survival of the cell.
Thus, to maintain the right number of histones, cells couple histone production temporally to DNA duplication so that they are only produced when they are needed. But how do they ensure that the right amount of histones is produced, even though protein production rate during S-phase depends on cell size and growth rate, and S-phase duration varies in different environmental conditions? We aim to understand how cells can produce the right number of histones independently of their size and how this regulation is affected by different environmental conditions. By understanding the cell-size-dependent regulation of histones, we expect to reveal regulatory processes that are broadly used by cells to adjust their protein content according to the requirements that go along with changes in cell size.
Relevant publications
People: Daniela, Dimitra, Arohi
Mitochondria are the powerhouses of cells. Mitochondrial DNA (mtDNA) is essential to mitochondria functions since it encodes for subunits of the respiratory chain. Defects in mtDNA maintenance and altered mtDNA copy number are linked to metabolic and neurodegenerative diseases, as well as many types of cancer. mtDNA replication mechanisms play a crucial role in maintaining the right mtDNA copy number and homeostasis.
When growing cells double in size, they need to ensure that also the amount of their DNA doubles. To achieve this, replication of nuclear DNA is coupled to cell cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mtDNA replication is not strictly coupled to the cell cycle and can occur throughout the cell cycle and even continue during long cell cycle arrests. How do cells ensure then that they produce the right amount of mtDNA? We found that mtDNA copy number increases with cell volume, which ensures constant concentrations. To understand mtDNA homeostasis during cell growth, we therefore now aim to reveal the molecular mechanisms that coordinate mtDNA amount with cell size.
Relevant publications
People: Anika, Francesco, Alissa
Single-cell microscopy is a powerful tool that we use across all our biological questions. Ranging from microfluidics-based live-cell microscopy to follow cell growth and division over multiple cell cycles, quantification of mitochondrial network and DNA in live cells to single molecule FISH, microscopy can provide direct quantitative insights. Despite recent progress in AI-based approaches, image analysis can be very time-consuming and is often still the rate-limiting step. To address this, we use state-of-the-art deep-learning to improve automated image analysis and work on making these approaches easily accessible for a broad community. We envision that standardized tools and approaches will enable reproducibility and data sharing.
Relevant publications
People: Francesco, Benedikt
Each cell in an organism has to control its size by balancing cell growth, division, and cell death. In particular, proliferating cells coordinate cell division with cell size and growth. In yeast as well as in humans, this coordination occurs in part at the G1/S transition: Cells that are smaller at their birth grow more before they divide compared to cells that are born bigger. Not surprisingly then, cancer cells – which lost the regulation of growth and division – often have altered and more variable sizes compared to healthy cells. Using live-cell time-lapse imaging combined with yeast genetics and molecular biology, we aim to understand the molecular processes through which cells can sense their own size, and adapt their size upon environmental changes such as changing nutrient conditions.
Relevant publications:
- Schmoller et al., Nature, 2015
- Chandler-Brown et al., Curr. Biol., 2017
- Schmoller, Curr. Opin. Cell Biol., 2017
- Swaffer et al., Mol. Cell, 2021
- Schmoller et al., MBoC, 2022
People: Yagya, Benedikt
For most proteins, the synthesis rate increases in direct proportion to the cell volume because also the limiting machinery for transcription and translation, including RNA polymerase and ribosomes, increases in abundance as cells get bigger. This means that more proteins are produced when the cell grows bigger and thereby, stable protein concentrations can be maintained. However, histone proteins, which bind to the DNA to pack it into the nucleus, this machinery-limited regulation is not appropriate, because rather than constant concentrations, the cell needs histone amounts that are proportional to the DNA content.
If too many histone proteins are produced but the DNA amount stays the same, the DNA gets more compacted, and highly condensed DNA forms an obstacle for many cellular processes. In contrast, too few histones would lead to loosely packed DNA that can be processed without any control. Both scenarios would harm the integrity and survival of the cell.
Thus, to maintain the right number of histones, cells couple histone production temporally to DNA duplication so that they are only produced when they are needed. But how do they ensure that the right amount of histones is produced, even though protein production rate during S-phase depends on cell size and growth rate, and S-phase duration varies in different environmental conditions? We aim to understand how cells can produce the right number of histones independently of their size and how this regulation is affected by different environmental conditions. By understanding the cell-size-dependent regulation of histones, we expect to reveal regulatory processes that are broadly used by cells to adjust their protein content according to the requirements that go along with changes in cell size.
Relevant publications
People: Daniela, Dimitra, Arohi
Mitochondria are the powerhouses of cells. Mitochondrial DNA (mtDNA) is essential to mitochondria functions since it encodes for subunits of the respiratory chain. Defects in mtDNA maintenance and altered mtDNA copy number are linked to metabolic and neurodegenerative diseases, as well as many types of cancer. mtDNA replication mechanisms play a crucial role in maintaining the right mtDNA copy number and homeostasis.
When growing cells double in size, they need to ensure that also the amount of their DNA doubles. To achieve this, replication of nuclear DNA is coupled to cell cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mtDNA replication is not strictly coupled to the cell cycle and can occur throughout the cell cycle and even continue during long cell cycle arrests. How do cells ensure then that they produce the right amount of mtDNA? We found that mtDNA copy number increases with cell volume, which ensures constant concentrations. To understand mtDNA homeostasis during cell growth, we therefore now aim to reveal the molecular mechanisms that coordinate mtDNA amount with cell size.
Relevant publications
People: Anika, Francesco, Alissa
Single-cell microscopy is a powerful tool that we use across all our biological questions. Ranging from microfluidics-based live-cell microscopy to follow cell growth and division over multiple cell cycles, quantification of mitochondrial network and DNA in live cells to single molecule FISH, microscopy can provide direct quantitative insights. Despite recent progress in AI-based approaches, image analysis can be very time-consuming and is often still the rate-limiting step. To address this, we use state-of-the-art deep-learning to improve automated image analysis and work on making these approaches easily accessible for a broad community. We envision that standardized tools and approaches will enable reproducibility and data sharing.
Relevant publications
People: Francesco, Benedikt
The Schmoller Lab
Recent Publications
Read more
epigenetics@HelmholtzMunich