Mechanisms by which chromatin modulates gene expression.

细胞中的基因表达发生在存储基因的细胞核中。在细胞核中，DNA不是以游离形式存在，而是被等量的蛋白质覆盖，形成一种称为染色质的结构。染色质是由重复的、间隔规则的亚基组成的周期性结构，亚基是核小体。核小体由一组包裹着DNA的蛋白质(组蛋白)组成。核小体既能阻断基因表达，又能激活基因表达。因此，染色质的一个重要功能是严格调控基因的表达，这对生物体的正常发育至关重要。当基因表达不能被染色质准确控制时，发育缺陷或癌症可能是由于产生错误的蛋白质造成的。为了控制正确的基因表达，必须在细胞中操作高度特异的机制，在发育过程中的精确时间移除或修改特定基因的核小体。我们认为重要的一种机制是改变核小体的组成。在细胞中，这可以通过用这些组蛋白的不同特殊形式(变体)来替代组蛋白来实现。我们认为，这些组蛋白变体可以特异性地产生染色体结构域，在某些情况下可以暴露或隐藏某些基因，从而打开或关闭它们。我们将采用一种新的方法，研究其中一个组蛋白变体，以发现它在决定所形成的染色体结构域的类型中所起的作用，以及这个结构域在不同特化细胞类型形成过程中的早期发育的精确时间开启或关闭基因的作用。这一新信息可能定义了在癌症进展或异常发育过程中防止错误基因表达的目标。

Gene expression in a cell occurs in the nucleus where genes are stored. In the nucleus, DNA is not in a free form but is covered with an equivalent weight of protein to form a structure known as chromatin. Chromatin is a periodic structure made up of repeating, regularly spaced subunits, the subunit being the nucleosome. A nucleosome consists of a group of proteins (histones) wrapped around with DNA. A nucleosome is both capable of blocking and activating gene expression. Therefore one important function of chromatin is to tightly regulate gene expression which is essential to allow an organism to develop properly. When gene expression is not accurately controlled by chromatin developmental defects or cancer can result from the production of incorrect proteins. To control correct gene expression, highly specific mechanisms must operate in the cell to remove, or modify, nucleosomes at certain genes at a precise time during development. One mechanism that we believe to be important is changing the make-up of a nucleosome. This can be achieved in the cell by the replacement of histones with different specialized forms of these histones (variants). We believe that these histone variants can specifically generate chromosomal domains which could in some cases expose or in other cases hide certain genes and thereby turn them on or off. Employing a new approach, we will study one of these histone variants to discover the role it plays in determining the type of chromosomal domain made and the role of this domain has in turning genes on or off at precise times in early development during the formation of different specialized cell types. This new information may define targets for the prevention of incorrect gene expression during cancer progression or abnormal development.