enhancer insulator promoter enhancer repressors. Insulator elements ran block this spreading, so insulators protect genes bom both indiscriminate activation and repression.

This situation lias consequences for some experimental manipulations. A gene inserted at random into the mammalian genome is often "silenced" because it becomes incorporated into a particularly dense form of chromatin called heterochromatin. But if insulators are placed up- and downstream of that gene they protect it from silencing.

Appropriate Regulation of Some Groups of Genes Requires Locus Control Regions

The human glob in genes are expressed in red blood cells of adults and in various cells in the lineage that forms red blood cells during development, There are five different globin genes in humans (Figure 17-13a). Although clustered, these genes are not all expressed at the same time. Rather, the different genes are expressed at different stages of development Starting with e, then the y genes, followed by J3 and fv How is their expression regulated?

Each gene has its own collection of regulatory sites needed to switch that gene on at the right time during development and in the proper tissues. Thus the p-globin gene (which is expressed in adult bone marrow) has two enhancers: one upstream of the promoter, the other downstream. Only in adult bone marrow are the correct regulators all active and present In appropriate concentrations to bind these enhancers. But morn than this is required to switch on these genes in the correct order.

A group of regulatory elements collectively called the locus control region, or LCR, is found 30—50 kb upstream of the whole cluster of globin genes. How the LCR works is still unclear, but it binds regulatory proteins diat cause the chromatin structure around the whole globin gene cluster to "open up," allowing access to the array of regulators that control expression of the individual genes in a defined order.

locus control region (LCR)

cluster of globin genes

10 kb cluster of globin genes

10 kb

b mouse ß-globin locus

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