Like mother, like daughter– Cells pass on metabolic transcriptional memory to their progeny

The capacity to remember is essential for all living beings. Memory enables us to rethink a certain experience and react accordingly. Moreover, it allows a parent to pass on this life experience to their kids, for example not to touch the oven plate because it is hot. On a certainly different level, cells are also able to remember how they reacted to a specific circumstance. This “transcriptional memory” enables the cell and by extension the organism to adapt to changing environments such as food availability. But do cells pass on their memories to their progeny as well? A team of researchers, with Dr. Poonam Bheda and Prof. Robert Schneider from the Institute of Functional Epigenetics (IFE) of Helmholtz Zentrum München leading the way, focused on this question and published their recent findings in Molecular Cell.

@Molecular Cell; Poonam Bheda 2020

The process of transcription, whereby our genetic information stored in DNA is transferred to RNA molecules so that proteins can be made, is essential for every cell of a living organism. As a result, transcription is tightly regulated to avoid any errors. Since cells of different tissues, such as heart or liver, do not require the same proteins, they only transcribe the set of genes that is needed for their function. However, the set of genes used by a cell can be extended or modified depending on the cellular needs, for example as a response to environmental or nutritional changes.

Epigenetic mechanisms are required for environmental adaptation.

In eukaryotes, such as plants, fungi and animals, the DNA is packaged into a structure called chromatin to fit into the tiny nucleus of the cell. The chromatin structure is an essential means for regulating transcription of genes. Through epigenetic mechanisms, a specific part of chromatin can be opened or closed and thereby become – or not – accessible for the transcription machinery. Epigenetic mechanisms thus function like a key - without it you cannot open or close the door. The chromatin states can be adapted to the cellular needs and consequently also changed as a response to environmental stimuli. The capacity to remember the transcriptional response to a certain stimulus enables cells to react faster if they encounter the same stimulus again. This so called transcriptional reinduction memory is advantageous for cell survival and identity in all living organisms, and in humans it is thought to be implicated in environmentally triggered diseases, such as diabetes. Thus, a comprehensive understanding of how transcriptional memory is regulated and whether it is passed on from a cell to its progeny is key to understanding the transmission of disease states from cell to cell.Therefore, researchers from all around the world teamed up and developed and applied a novel and innovative workflow combining microfluidics with single-cell live imaging to monitor transcriptional changes within cells. This enabled them to construct pedigrees and analyze transcriptional reinduction memory in single cells over multiple generations for the first time. “Microfluidics traps individual cells in microchannels, which makes it possible to monitor their behavior and importantly to trace their ancestry”, said Dr. Poonam Bheda.

The inheritance of transcriptional memory is regulated by epigenetic mechanisms.

The researchers studied the transcriptional reinduction memory of the galactokinase GAL1* gene in yeast. They found that mother cells can build a memory to a specific nutritional stimulus but also that their naive daughter cells follow their mother’s footsteps and respond equally to the same stimulus. To determine how transcriptional memory and its inheritance is regulated the team performed a high-throughput screen to identify factors controlling this “memory”. “We focused on chromatin factors because we hypothesized that epigenetic mechanisms would regulate memory of metabolic states, and sure enough this is what we found”, said Prof. Robert Schneider, who led the work and is the Director of the Institute of Functional Epigenetics at Helmholtz Zentrum München. “Epigenetic mechanisms are by themselves heritable”, adds Bheda. “Thus, we were eager to investigate whether the inheritance of transcriptional memory depends on potentially heritable chromatin factors and modifications.”

Altogether, this work not only provides an important new tool to study transcriptional memory, but it also enables the dissection of memory maintenance and inheritance. “Our study is just a starting point”, anticipates Prof. Antonis Kirmizis, a Group Leader from the University of Cyprus who co-led these studies and is a co-corresponding author. “For example, in humans, transcriptional memory might be a driver of diabetes progression. The reaction of cells to high blood sugar** has tremendous effects on the patients because cells can become resistant to insulin. Our approach could be used to characterize these cells and to uncover the molecular mechanisms behind insulin resistance for example, and maybe in doing so, contribute to the development of further diabetes therapies.”

Further information:

* In yeast, galactose is the non-preferred carbon source for growth. However, in case glucose is not available, yeast metabolizes galactose to extract energy. Therefore, they express different enzymes that break down galactose including the galactokinase GAL1. Cells that have never been in contact with galactose need some time until the galactose-metabolism machinery starts, whereas cells that had to switch on the machinery before can react faster when they are exposed to galactose again.

** In human, high blood sugar levels (hyperglycemia), even if only for a short period, can cause metabolic memory that leads to long-lasting complications. These effects are largely irreversible, even if the sugar levels are under control, and accumulate to drive obesity, diabetes, and ageing.