Epigenetic Memory Phenomenon Each cell type has a specific epigenome which is configured by the aforementioned alterations in chromatin level DNA methylation histone modifications and small non coding RNAs The combination and interaction of these alterations form the structure of chromatin In the case of pluripotent cells the configuration of chromatin is open and not compacted allowing post translational modifications during cell differentiation The switching from pluripotent to specialized cells is conducted according to the form of chromatin domains close to the transcription start sites TSS of genes which will determine the expression suppression of genes associated with development 19 20 As it was mentioned before induced pluripotent cell lines collect many aberrations in a genetic and epigenetic level during reprogramming These aberrations along with the pre existing maintained epigenetic markers of somatic cells can modify the epigenome and transcriptome of iPS cells When this modified epigenome is inherited by the iPSCs it is called epigenetic memory 6 21 22 Although iPSCs are pretty similar to ESCs there seem to be some small differences in transcription and epigenetic level These changes have been revealed from several analyses in the DNA methylation level of iPSCs and specifically in the cytosine methylation of CpG nucleotides
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These nucleotides are present close to gene promoters regions and when these regions are hyper methylated the corresponding genes are repressed 23 One of these studies revealed that genes which were specific for the specialization of a cell type are maintained under reprogrammed during the process of reprogramming of iPSCs 6 Another study between the methylation profiles of iPSCs and ESCs demonstrated that the highly methylated regions in ESCs are located mainly in close regions of gene promoters while the highly methylated regions in iPSCs localize in distal regions of gene promoters and intergene regions 24 Effect of the epigenetic memory on iPSC differentiation The alterations that are caused by epigenetic memory phenomenon might be minimal but can lead to crucial changes in the characteristics of cells In general the process of reprogramming is affected by the formation of differentially methylated regions DMRs of chromatin These regions depend on the initial cell type the method of reprogramming and the culture conditions
The majority of them is derived from de novo aberrant methylation patterns while the rest of them result from the phenomenon of epigenetic memory which includes the original type of somatic cell as well as the methylation pattern in the autologous cells DMRs that derive from epigenetic memory can create a change in the differentiation spectrum of induced pluripotent cells and force them to differentiate into adult cells of the initial type 25 Artificial conditions such as culture conditions and chemical agents can affect the epigenetic memory markers and consequently the reprogramming ability of cells Specifically the duration and the conditions of culturing can affect this process since it takes a specific number of replication runs so that reprogramming is complete These replication runs are called passages and the higher the number of them the less epigenetic differences there are 22 According to a methylation pattern study while the number of passages increases the DMRs of human iPSCs get reduced and the efficiency of a line to differentiate into any of the three germ layers with the same effectiveness rises 9 Moreover the number of passages which is mandatory to eradicate molecular and epigenetic alterations is associated with the initial type of somatic cells 22 Chemical agents in combination or without with culture conditions can also affect epigenetic memory of iPSCs For example 5 azacytidine AZA and trichostatin histone deacetylase inhibitor can prohibit DNA methylation by prohibiting DNA methyltransferase 1 10 Also another enzyme DNA hydroxylase Tet1 can promote reprogramming process by oxidizing regions of methylations and causing demethylation 26 Moreover it is proven that vitamin C can induce hypo methylation and increase the activity of histone H3K36 demethylase which will eventually lead to more efficient reprogramming 11 Conclusions The use of iPSCs in the field of Regenerative Medicine and Pharmacology is a really promising and innovative approach Nonetheless there are still some limitations that need to be overcome so that this approach is totally effective
One of the major limitations is the epigenetic memory phenomenon According to this phenomenon epigenetic marks of the initial cell type remain in iPSCs and force them to differentiate into adult cells of the original type A bioinformatics meta analysis of DNA methylation and transcription patterns of iPS cell lines could reveal hot spots of under reprogramming that come up during reprogramming process and genes with epigenetic signatures that are inherited from somatic cells of the original cell type In that way the direction of cell differentiation could be anticipated and even altered to the desirable cell type by using several means such as chemical agents after the study of the genes influenced by epigenetic memory at a functional level Thus this approach to the limitation of epigenetic memory phenomenon could be transformed into an advantage regarding to the use of iPSCs 4 25
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