January 20, 2009 -- Epigenetic finding adds insight on how cells become brain, liver -- and malignant
at Johns Hopkins have found that the gradual maturing of embryonic
cells into cells as varied as brain, liver and immune system cells is
apparently due to the shut off of several genes at once rather than in
individual smatterings as previous studies have implied.
Working with mouse brain and liver cells, as well as embryonic stem
cells, Johns Hopkins University School of Medicine professor Andrew
Feinberg, M.D., M.P.H., led an investigation of a kind of epigenetic
modification to histones, the molecular "spools" that DNA winds around
in the cell nucleus. This modification is a variety of the so-called
epigenetic changes that alter the function of cells without directly
altering the nuclear DNA in the cells.
Other scientists had
previously found that histone modifications appear to silence
individual genes in the DNA that coils around affected histones. But
when Feinberg and his team compared the activity of thousands of genes
in the liver and brain cells, they found that a particular modification
- in which two methyl groups clip onto histones - seemed to silence
long stretches of DNA containing many genes at once. The findings will
publish in Nature Genetics online on Jan. 18.
Since the silenced
stretches varied greatly between the different types of cells,
Feinberg, postdoctoral fellow Bo Wen, and their colleagues wondered
whether these sections - called large organized chromatin K9
modifications, or LOCKS - might be responsible for the transition from
the "blank slate" quality of embryonic cells to the specialized
functions that mature cells take on. To find out, he and his team
looked for LOCKs in mouse embryonic stem cells. Unlike mature, adult
liver and brain cells, in which about 40 percent of the genome was
silenced by LOCKs, the embryonic stem cells had no LOCKs.
the researchers compared the regions of DNA affected by LOCKs between
mouse liver and brain cells and their corresponding human cells. The
same cell types in both organisms had remarkably similar regions of DNA
silenced by LOCKs, suggesting that the same genes necessary to control
cell function are affected in mice and people.
suggest that LOCKs appear gradually during development, refining cells'
functions as they differentiate into particular cell types," Wen says.
"Our experiments suggest that the whole forest of genes is changing,
but people have been looking at the individual trees."
epigenetic changes also are known to play a role in abnormal cell
growth, the researchers suspected that LOCKs were involved in the
development of cancer. When they looked for genes in several common
cancer cell lines often used in research, they indeed found
significantly fewer LOCKs than in normal liver and brain cells.
cancer, some of these LOCKs may become unlocked," says Feinberg.
"Sections of DNA that were silenced in a cell type might become active,
giving cancer cells characteristics of other cell types that they're
not supposed to have."
Feinberg says this "unlocking" might
cause cancer cells to revert to a more immature developmental state,
explaining some of their unusual behavior, such as extreme
proliferation or migration to different areas of the body.
Source : Johns Hopkins Medical Institutions