There are several pieces of evidence indicating that the number of specific histone modifications like the bivalent marks in Embryonic Stem Cells (ESCs) and their position in the genome relies on the recruitment of enzymes that speeds up the modification. Moreover, it also depends on the level of demethylases, speed of cell cycle, and the metabolic state of the cell. With the help of advanced VTM kits and other clinical tools, the molecular processes that govern stem cell maintenance and differentiation are studied.
Metabolic Effects On Histone Modifications
All enzymes that modify the histone along with the enzymes that remove modifications depend on the some important metabolites like acetyl-CoA, S-adenosyl methionine (SAM), NAD, and 2 oxoglutarate. In these metabolites, the intracellular concentrations highly rely on the physiological status of the cell and presence of nutrient availability.
In majority of the stem cells, there’s a specialised metabolism as they are more dependent on glycolysis and rely relatively less on oxidative phosphorylation to produce energy. Furthermore, the mouse Embryonic Stem Cells (mESCs) rely on Thr and hESCs (human Embryonic Stem Cells) on Met to make sure their pluripotency maintains. When these amino acids are taken out, it results in a drop in SAM levels and concomitantly of certain histone methylation sites like the H3K4. What’s more important is the fact that not only histone methylation but even the histone acetylation is impacted by stem cell-specific metabolic pathways. Stem cells general cytosolic acetyl-CoA through the glycolysis and resultantly, pyruvate-derived citrate flux comes due to ATP citrate lyase. If this pathway is blocked, there will be a significant decrease in histone acetylation and an early differentiation of hESCs will be seen. Studies have confirmed that global changes like differences in metabolism can result in very specific effects during cell differentiation.
Histone Post-Translational Modification Kinetics Across The Cell Cycle
Among the many global effects that influence the whole chromatin in the nucleus, is the cell cycle. Inside every cycle, there are newly formed and largely unmodified histones that fix into the DNA due to which there’s an overall dilution of most histone modifications. In the newly formed chromatin, 50% of the histone H3 molecules carry H3K18/K23ac, H3K9me1, and H3K14ac, while the remaining half of the H4 molecules carry H4K5ac and H3K12ac. They are at levels where they closely mirror the growth and modification pattern of soluble histones in pre-deposition complexes. This indicates that all the post-translational modifications are maintained inside the first few minutes of incorporation. When the chromatin is maturing, K27me1, K36me1, and K27me2 find their place on the new histones. This occurs quickly after deposition onto newly replicated DNA, begging for a fast deposition. That said, more methylations on heterochromatic marks are also imposed on the fresh incorporated histones, but with slower kinetics making it similar to the cell cycle. Over here, the length of the cell cycle is a very crucial regulator. (Moritz, et al. 2020)
Current Implications and Treatments according to Epigenetics and Histone Modification in Stem Cells
Stem cells are a very strong and promising tool for new medical concepts that support cellular therapy in various human illnesses and injuries. Several human cancers are fed by a tiny population of cancer stem cells (CSCs) and these cells are a huge obstacle in tumor treatment. In order to better understand the mechanisms attached with stemness and self-renewal along with the self-renewal and cell differentiation is also needed to translate this knowledge into medical applications.
Cancer Stem Cells
These stem cells have a very small subpopulation of cells often seen in the particular niches of some tumor types. Contrary to normal stem cells where the cell-cycle transitions are strictly regulated, CSCs carry several pro-oncogenic mutations. These mutations enable very strong proliferation that facilitates capacity for the reconstituting differentiated tumor in transplantation, asymmetric division, resistance to conventional therapies, and taking part in the epithelial-mesenchymal transition. With the help of these properties, Cancer Stem Cells can improve and maintain malignant phenotypes. They are linked to tumor aggressiveness, disease stage, onset of relapse and metastasis, heterogeneity, and poor medical outcome. (Battle and Clevers 2017)