Studies indicate stem cells are flexible enough to become any cell in the body

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Studies indicate stem cells are flexible enough to become any cell in

the body

http://www.news-medical.net/?id=17607

Two studies in the April 21, 2006 Cell report new details of

the " genetic program " that affords embryonic stem cells the

flexibility to give rise to any cell type in the body. Both groups

identified mechanisms by which the embryonic stem cells of mice or

humans keep from going down any one particular developmental path--

that of muscle or nervous tissue, for example--while

remaining " poised for activation. "

Human embryonic stem cells can be kept in an undifferentiated state

and selectively induced to form many specialized cell types, which

could potentially replace cells lost or damaged by disease. The new

findings may therefore aid in the realization of embryonic stem

cells' therapeutic potential for regenerative medicine, according to

the researchers, while furthering scientists' understanding of early

development.

In one of the studies, Young of the Whitehead Institute, and

his colleagues, found that a member of the so-called Polycomb-group

proteins is distributed across a special set of more than 200

developmental genes in human embryonic stem cells. Polycomb proteins

are known to silence gene activity through chemical, or " epigenetic, "

modifications that alter the way that DNA is packaged into chromatin.

" We saw that the Polycomb protein preferred to occupy genes for most

of the human developmental regulators to repress their activity, "

Young said. " These genes encode transcription factors that control

development downstream of the embryo. "

" This makes sense because were the developmental transcription

factors 'on,' they would cause the embryonic stem cells to

differentiate into specific cell types. It's an exciting result

because it appears that the Polycomb proteins are generally

responsible for maintaining developmental genes in an 'off' state. "

Developmental genes found in association with the Polycomb protein

were also occupied by histone proteins chemically modified at sites

known to repress gene activity, they found. Histones--the chief

proteins of chromatin--act as spools around which DNA winds and play

a role in gene regulation.

Furthermore, they found, the silenced developmental genes became

preferentially activated in human embryonic stem cells undergoing

differentiation.

The findings help to explain earlier results in mice deficient for

Polycomb proteins, Young said. The embryonic stem cells of those mice

were " extremely unstable " and tended to specialize or die in culture,

he said.

The results also add to the team's earlier finding, reported in Cell

last year, that a trio of transcription factors--Oct4, Sox2, and

nanog--are key regulators of embryonic stem cells' pluripotency and

self-renewal, " he said. Pluripotency refers to the cell's ability to

develop into multiple cell types. The three factors apparently work

together to activate pathways critical for stem cell identity, while

repressing those leading to differentiation.

The researchers now report that the stem cell regulators Oct4, Sox2,

and nanog co-occupy " a significant subset " of the developmental genes

that are repressed by the Polycomb protein, further supporting a link

between repression of developmental regulators and embryonic stem

cell identity.

" This paper connects the two classes of embryonic stem cell

regulators and provides a foundation for understanding the basic

circuitry underlying human development, " Young said.

In the second paper, Bradley Bernstein of Massachusetts General

Hospital and Harvard Medical School, and his colleagues, report the

discovery of a unique chromatin structure that marks key

developmental genes in embryonic stem cells. The structure, which

they call " bivalent domains, " includes a pattern of chemical

modification with both repressive and activating characteristics.

" In differentiated cells, chromatin is either 'on' or 'off' in

accordance with the identity of that particular cell--rarely or never

in between, " Bernstein said.

" In embryonic stem cells, we found a totally different structure. The

developmental genes of stem cells bear evidence of both active and

repressive states. It's the first time this has been seen. "

The genes appeared to be in a silent state, he explained, but with an

activating influence that could allow them to turn on rapidly as

needed. He suggested that by preserving the potential of key

developmental genes, the bivalent domains may contribute to the

unique ability of embryonic stem cells to form the many different

tissues in the body.

When the researchers examined the state of the same genes in a

collection of differentiated cell types, they found that the bivalent

domains had been replaced by either repressive or activating

modifications, in accordance with the cell's identity. Muscle cells,

for example, must express the master genes for muscle, while

silencing those specifically required for other cell types, Bernstein

explained.

The team suggests that a comprehensive inventory of the presence or

absence of bivalent domains over key developmental genes may provide

valuable markers of cell identity and differentiation potential, in

both health and disease. Bernstein said the findings also suggest

that therapies that modify cells' epigenetic state might prove useful

in the field of regenerative medicine.

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