Editing Cellular differentiation (section)

===Importance of epigenetic control===

The first question that can be asked is the extent and complexity of the role of epigenetic processes in the determination of cell fate. A clear answer to this question can be seen in the 2011 paper by Lister R, ''et al.'' <ref name = "Lister">{{cite journal | vauthors = Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O'Malley R, Castanon R, Klugman S, Downes M, Yu R, Stewart R, Ren B, Thomson JA, Evans RM, Ecker JR | title = Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells | journal = Nature | volume = 471 | issue = 7336 | pages = 68–73 | date = March 2011 | pmid = 21289626 | pmc = 3100360 | doi = 10.1038/nature09798 | bibcode = 2011Natur.471...68L }}</ref> on aberrant epigenomic programming in [[human]] [[induced pluripotent stem cells]]. As induced pluripotent stem cells (iPSCs) are thought to mimic [[embryonic stem cells]] in their pluripotent properties, few epigenetic differences should exist between them. To test this prediction, the authors conducted whole-genome profiling of [[DNA methylation]] patterns in several human embryonic stem cell (ESC), iPSC, and progenitor cell lines.

Female [[adipose]] cells, [[lung]] [[fibroblasts]], and foreskin fibroblasts were reprogrammed into induced pluripotent state with the [[OCT4]], [[SOX2]], [[KLF4]], and [[MYC]] genes. Patterns of DNA methylation in ESCs, iPSCs, somatic cells were compared. Lister R, ''et al.'' observed significant resemblance in methylation levels between embryonic and induced pluripotent cells. Around 80% of [[CpG site|CG dinucleotides]] in ESCs and iPSCs were methylated, the same was true of only 60% of CG dinucleotides in somatic cells. In addition, somatic cells possessed minimal levels of [[cytosine methylation]] in non-CG dinucleotides, while induced pluripotent cells possessed similar levels of methylation as embryonic stem cells, between 0.5 and 1.5%. Thus, consistent with their respective transcriptional activities,<ref name= "Lister"/> DNA methylation patterns, at least on the genomic level, are similar between ESCs and iPSCs.

However, upon examining methylation patterns more closely, the authors discovered 1175 regions of differential CG dinucleotide methylation between at least one ES or iPS cell line. By comparing these regions of differential methylation with regions of cytosine methylation in the original somatic cells, 44-49% of differentially methylated regions reflected methylation patterns of the respective progenitor somatic cells, while 51-56% of these regions were dissimilar to both the progenitor and embryonic cell lines. [[In vitro]]-induced differentiation of iPSC lines saw transmission of 88% and 46% of hyper and hypo-methylated differentially methylated regions, respectively.

Two conclusions are readily apparent from this study. First, epigenetic processes are heavily involved in [[cell fate determination]], as seen from the similar levels of cytosine methylation between induced pluripotent and embryonic stem cells, consistent with their respective patterns of [[Transcription (genetics)|transcription]]. Second, the mechanisms of reprogramming (and by extension, differentiation) are very complex and cannot be easily duplicated, as seen by the significant number of differentially methylated regions between ES and iPS cell lines. Now that these two points have been established, we can examine some of the epigenetic mechanisms that are thought to regulate cellular differentiation.