Discovery brings embryonic stem cell medicine a step closer

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Discovery brings embryonic stem cell medicine a step closer

http://www.news-medical.net/?id=17608

A team of scientists announced a critical step on the path of

realizing the promise of embryonic stem (ES) cells for medicine. As

described in the April 21 issue of Cell, the researchers have

discovered unique molecular imprints coupled to DNA in mouse ES cells

that help explain the cells' rare ability to form almost any body

cell type. These imprints, or " signatures, " appear near the master

genes that control embryonic development and probably coordinate

their activity in the early stages of cell differentiation. Not only

do these findings help to unlock the basis for ES cells' seemingly

unlimited potential, they also suggest ways to understand why

ordinary cells are so limited in their abilities to repair or replace

damaged cells.

" This is an entirely new and unexpected discovery, " said Brad

Bernstein, lead author of the study, assistant professor at

Massachusetts General Hospital and Harvard Medical School, and a

researcher in the Chemical Biology program at the Broad

Institute. " It has allowed us to glimpse the molecular strategies

that cells use to maintain an almost infinite potential, which will

have important applications to our understanding of normal biology

and disease. "

Chromatin-the protein scaffold that surrounds DNA - acts not only as

a support for the double helix but also as a kind of

gene " gatekeeper. " It accomplishes the latter task by selecting which

genes to make active or inactive in a cell, based on the nearby

chemical tags joined to its backbone. By examining the chromatin in

mouse ES cells across the genome, the scientists discovered an

unusual pair of overlapping molecular tags in the chromatin

structure, which together comprise what they called a " bivalent

domain, " reflecting the dual nature of its design. These domains

reside in the sections of chromatin that control the most

evolutionarily conserved portions of DNA, particularly the key

regulatory genes for embryonic development.

" These signatures appear frequently in ES cells, but largely

disappear once the cells choose a direction developmentally, " said

Bernstein. " This suggests they play a significant role in regulating

the cells' unique plasticity. "

The remarkable design of bivalent domains, which has not been

previously described, merges two opposing influences - one that

activates genes and another that represses them. When combined in

this way, the negative influence seems to prevail and, as a result,

the genes positioned near bivalent domains are silenced. However, the

activating influence appears to keep the genes poised for later

activity. " For genes, this is equivalent to resting one finger on the

trigger, " said Stuart Schreiber, an author of the Cell paper, the

director of the Chemical Biology program at the Broad Institute, and

professor at Harvard University. " This approach could be a key

strategy for keeping crucial genes quiet, but primed for when they

will be most needed. "

Although most people think of heredity in terms of DNA and the genes

encoded by it, chromatin also carries inherited instructions known

as " epigenetic " information. Thus, the chromatin scaffold (including

its bivalent domains) forms a sort of molecular memory that, along

with DNA, can be transferred from a cell to its descendants. Yet ES

cells signify the earliest cellular ancestors, leaving the question

of how epigenetic history first begins. The scientists found that

bivalent domains coincide with characteristic DNA sequences,

indicating that this molecular memory may originate from the DNA

itself. " How the initial epigenetic state is established and then

altered during development has implications not only for stem cell

biology, but also for cancer and other diseases where epigenetic

defects are implicated, " Bernstein said.

A related study led by Rick Young, a member of the Whitehead

Institute and an associate member of the Broad Institute, appears in

the same issue of Cell and describes new control features found in

human ES cells.

http://www.broad.mit.edu