Embryonic stem cells are capable of self-renewing and differentiating to the desired fate depending on their position in the body.
Stem cell homeostasis is maintained through epigenetic mechanisms that are highly dynamic in regulating the chromatin structure as well as specific gene transcription programs.
There has been multiple evidence suggesting that the maintenance of the lineage commitment of stem cells is controlled by epigenetic mechanisms such as DNA methylation, histone modifications and regulation of ATP-dependent remolding of chromatin structure.
This regulation of chromatin through epigenetic modifications is a molecular mechanism that determines whether the cell continues to differentiate into the desired fate.
[4] Embryonic stem cells exhibit dramatic and complex alterations to both global and site-specific chromatin structures.
Histones modifications in chromatin were analyzed at various time intervals (along a 6-day period) following the initiation of in vitro embryonic stem cell differentiation.
These results indicate a decrease in the level of active euchromatin epigenetic marks upon initiation of embryonic stem cell differentiation which is then followed immediately by reprogramming of the epigenome.
The global cytosine methylation pattern appears to be established prior to the reprogramming of the histone code that occurs upon in vitro differentiation of embryonic stem cells.
Khavari et al. discussed the fundamental mechanisms of DNA methylation and the interaction with several pathways regulating differentiation.
These studies point to the importance of the interaction of DNMTs in order to maintain stem cell states allowing for further differentiation and formation of heterochromatin to occur.
Okamoto et al. previously documented the expression level of the Oct4 gene decreasing with embryonic stem cell differentiation.
This conclusion was further supported by the finding in the same paper that 2i ESCs gained primed-like qualities after removing a functional PRC2 complex, which rendered H3K27me3 useless.
The western analysis showed the lack of initial deacetylation on Day-1 which, was observed in the control for the embryonic stem cell differentiation.
[citation needed] Alkaline phosphatases found in humans are membrane bound glycoproteins, which function to catalyze the hydrolysis of monophosphate esters.
The continued culture of HDAC1 knockout embryonic stem cells showed that the embryoid bodies formed became irregular and reduced in size rather than uniformly spherical as in normal mice.
They were able to determine this by mapping OSKM-binding chromatin states in reprogramming stages and doing loss and gain of function experiments.
They were also able to conclude that OSK silenced ME (MEF-enhancers) partially through Hdac1, which suggests that Hdac1 plays a role in the process of reprogramming somatic cells.
As such, studies done on small molecules or drugs that inhibit epigenetic mechanisms during differentiation can have great potential for clinical applications such as bone regeneration from mesenchymal stem cells.
developed a theoretical/mathematical framework for this, which is significant because it is one of the first attempts to link the Waddington landscape idea with gene regulatory networks in a data-driven way.
Any disturbance of a stable epigenetic regulation of gene expression mediated by DNA methylation is associated with a number of human disorders, including cancer as well as congenital diseases such as pseudohypoparathyroidism type IA, Beckwith-Wiedemann, Prader-Willi and Angelman syndromes, which are each caused by altered methylation-based imprinting at specific loci.
Perturbations of both global and gene-specific patterns of cytosine methylation are commonly observed in cancer while histone deacetylation is an important feature of nuclear reprogramming in oocytes during meiosis.
[18] Recent studies have revealed that there is an array of different pathways that cooperates with one another in order to bestow proper epigenetic regulation by DNA methylation.
Addressing these questions will help extend insight into these recent findings for a central role in epigenetic regulators of DNA methylation in controlling embryonic stem cell differentiation.