Dedicated to the acceptance, medical treatment, & legal protection of individuals in the process of correcting the misalignment of their anatomical sex, & supporting their transition into society.
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San Franciso, CA, USA. Scientists have identified about two dozen genes that control embryonic stem cell fate. The genes may either prod or restrain stem cells from drifting into a kind of limbo, they suspect. The limbo lies between the embryonic stage and fully differentiated, or specialized, cells, such as bone, muscle or fat.
The new findings come from the first large-scale search for genes crucial to embryonic stem cells. The research was carried out by a team at the University of California, San Francisco (UCSF) and reported in the journal Cell.
An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity. Thomas G. Fazzio, Jason T. Huff, and Barbara Panning. Cell 134 162-174.
By knowing the genes and proteins that control a cell's progress toward the differentiated form, researchers may be able to accelerate the process. There are important potential benefits from the finding: a better understanding of how cell differentiation affects the prevalence of birth conditions, the study of some degenerative diseases, or the use of stem cells in therapy.
Barbara Panning, PhD, is a UCSF associate professor of biochemistry and biophysics, and the paper's senior author. She has done foundational research on decipherig commands that control the X chromosome shutdowns in the cells of every human female. Photo by Robert Foothorap.
"The genes we identified are necessary for embryonic stem cells to maintain a memory of who they are," says Panning. "Without them the cell doesn't know whether it should remain a stem cell or differentiate into a specialized cell."
The scientists used a powerful technique known as RNA interference, or RNAi, to screen more than 1,000 genes for their role in mouse embryonic stem cells. RNAi is a gene-silencing process that inhibits gene expression by causing the degradation of specific RNA molecules or hindering the transcription of specific genes. The technique allows researchers to "knock down" individual genes, reducing their abundance in order to determine the gene's normal role.
The RNAi Process. Small RNA molecules activate a cellular response to destroy a specific mRNA.
Image courtesy of Richard Robinson; adapted under a Creative Commons Attribution License.
Source: RNAi Therapeutics: How Likely, How Soon? Richard Robinson PLoS Biology 2(1) e28 doi: 10.1371/ journal.pbio.0020028
The research focused on proteins that help package DNA. In the nucleus, DNA normally wraps around protein complexes called nucleosomes, forming a structure known as chromatin. This is what makes up chromosomes.
They found 22 proteins, each of which is essential for embryonic stem cells to
maintain their consistent shape,
growth properties, and
pattern of gene expression.
Most of the genes code for multi-protein complexes that physically rearrange, or "remodel" nucleosomes, changing the likelihood that the underlying genes will be expressed to make proteins.
The main player they identified is a 17-protein complex called Tip60-p400. This complex is necessary for the cellular memory that maintains embryonic stem cell identity, Panning explains. Without it, the embryonic stem cells turned into a different cell type, which had some features of a stem cell but many features of a differentiated cell.
The scientists believe that Tip60-p400 is necessary for embryonic stem cells to correctly read the signals that determine cell type. These findings are not only important for understanding cellular memory in embryonic stem cells, but will also likely be relevant to other cell types, they say.
Inactivation of other genes disrupted embryonic stem cell proliferation. These genes were already known to have only slight influence on viability of mature cells in the body. This suggests that embryonic stem cells are "uniquely sensitive to certain perturbations of chromatin structure," the scientists report.
If other types of stem cells are also found to be sensitive to these chromatin perturbations, this could lead to novel cancer therapies in the future, Panning says.
Lead author on the paper is Thomas G. Fazzio, PhD, a postdoctoral fellow. Co-author is Jason T. Huff, BSc, a graduate student. Both are in Barbara Panning's lab.
An RNAi Screen of Chromatin Proteins Identifies Tip60-p400 as a Regulator of Embryonic Stem Cell Identity. Thomas G. Fazzio, Jason T. Huff, and Barbara Panning. Cell 134 162-174.
Summary
Proper regulation of chromatin structure is necessary for the maintenance of cell type-specific gene expression patterns. The embryonic stem cell (ESC) expression pattern governs self-renewal and pluripotency. Here, we present an RNAi screen in mouse ESCs of 1008 loci encoding chromatin proteins. We identified 68 proteins that exhibit diverse phenotypes upon knockdown (KD), including seven subunits of the Tip60-p400 complex. Phenotypic analyses revealed that Tip60-p400 is necessary to maintain characteristic features of ESCs. We show that p400 localization to the promoters of both silent and active genes is dependent upon histone H3 lysine 4 trimethylation (H3K4me3). Furthermore, the Tip60-p400 KD gene expression profile is enriched for developmental regulators and significantly overlaps with that of the transcription factor Nanog. Depletion of Nanog reduces p400 binding to target promoters without affecting H3K4me3 levels. Together, these data indicate that Tip60-p400 integrates signals from Nanog and H3K4me3 to regulate gene expression in ESCs.
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Eliminating the overlap between civil unions and religious marriage will permit unmuddled decision making on our civil institutions and avoid the temptation of the state to interfere in matters of religious doctrine.
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The Overlap Between Civil Unions And Religious Marriage
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