Much (not all) of the information a cell needs to function is encoded in its DNA nucleotide sequence, i.e. the pattern of adenine, thymine, cytosine, and guanine subunits. However, plenty of biochemical information which is not encoded in the nucleotide sequence is nevertheless passed down to subsequent generations.
This is known as epigenetic inheritance. One of the most well-known variants of epigenetic inheritance is DNA methylation, i.e. affixing methyl (-CH3) chemical units to part of the DNA.
Epigenetic inheritance is a somewhat recent discovery, and many scientists are trying to figure out how it works. It isn't a simple "lab curiosity;" e.g. epigenetic mutations have been reported in children conceived during the Dutch Hunger Winter near the end of World War 2.
Epigenetics may be involved in stem cell differentiation into various specialized cell types, but the biochemical mechanisms often remain a mystery. In the long term, figuring out questions like these may help scientists use stem cells more effectively and safely for organ and tissue repair, provide insight into chemotherapy, and assist with may other useful medical applications.
Andrew Feinberg (John Hopkins University, United States) and coworkers have investigated the epigenetics of blood stem cell differentiation. They have shown how DNA methylation regulates the specialization of blood stem cells into leukocytes or lymphocytes, two different types of white blood cells.
Identifying relevant epigenetic biochemical markers.
The scientists utilized cell sorting and DNA analysis to characterize a range of mouse blood stem cells. Their goal was to identify how the cells' DNA differed from one another in terms of methyl chemical units affixed to CpG sites (cytosine directly linked to guanine in the same DNA strand).
CpG islands (e.g. regions of high CpG density) often indicate the start of a gene in mammals; thus, they can be used as a proxy for determining the starting location of a gene. This is how CpG methylation impacts the expression of a specific gene, thereby providing a means of epigenetic control over DNA expression.
The scientists found many differentially methylated regions in genes known to regulate blood stem cell differentiation. One example is Mpo, the gene which encodes for myeloperoxidase, an enzyme commonly found in a subtype of white blood cells (neutrophil granulocytes) which help to kill pathogens at the site of injuries.
At times, the scientists were able to assign an epigenetic role to genes of previously unknown function in stem cell differentiation. One example is the Gcnt2 gene, which controls the synthesis of a protein important in the development of blood type.
A trend was that the DNA of blood stem cells destined to become lymphocytes had more extensive DNA methylation than that of cells destined to become leukocytes. However, DNA methylation sometimes did not correlate with gene expression.
Implications.
How will scientists use this information to advance medicine? Chemotherapy agents which affect epigenetic expression should be tailored to either enhance or hinder it, depending on which gene expression control mechanism the cancer cells use to propagate themselves.
A further application is in stem cell therapy, which is sometimes ineffective or dangerous. Enhancing or hindering epigenetic expression may help scientists direct an undifferentiated stem cell into a specific type of cell, as long as the epigenetic modifiers of cellular differentiation are well-known.
NOTE: The scientists' research was funded by the National Institutes of Health, the Thomas and Stacey Siebel Foundation, the Leukemia and Lymphoma Society, and the California Institute for Regenerative Medicine. One of the scientists (Irving Weissman) has declared financial interest in this research.
for more information:
Ji, H., Ehrlich, L. I. R., Seita, J., Murakami, P., Doi, A., Lindau, P., Lee, H., Aryee, M. J., Irizarry, R. A., Kim, K., Rossi, D. J., Inlay, M. A., Serwold, T., Karsunky, H., Ho, L., Daley, G. Q., Weissman, I. L., & Feinberg, A. P. (2010). Comprehensive methylome map of lineage commitment from haematopoietic progenitors Nature : 10.1038/nature09367