As cells differentiate during embryogenesis and during differentiation from stem cells in adult organisms (see Chapter 21), many of the genes induced during the process are initially in repressed regions of heterochromatin in undifferentiated progenitor cells. Activation of these genes requires that the chromatin environment of their transcription-control regions become decondensed so that transcription factors can bind to enhancers and promoter-proximal control elements and so that the general transcription factors and Pol II can bind to promoters. In many cases, this decondensation is initiated by special pioneer transcription factors that can bind to their cognate binding sites in DNA even when those sites are within repressed heterochromatic regions of chromatin. These factors have a DNA-binding domain that binds to one side of the DNA helix in a manner similar to the bacteriophage 434 repressor (see Figure 9-29). This domain allows these factors to bind to their specific binding sites while the DNA is wrapped around a histone octamer with the opposite side of the DNA against the surfaces of histones.
One example of pioneer transcription factors initiating the process of transcriptional activation involves the liver-specific gene Alb1, encoding serum albumin, a major constituent of blood serum that is secreted into the blood by hepatocytes. In the developing mouse, the FoxA and GATA-4 or GATA-6 transcription factors are the first transcription factors to bind to an Alb1 enhancer in undifferentiated gut endodermal cells destined to develop into the liver. FoxA has a “winged helix” DNA-binding domain that binds to one side of the DNA helix containing the FoxA-binding site. GATA factors are also able to bind to their specific sites in DNA when those sites are included in nucleosomal DNA wrapped around a histone octamer. The FoxA and GATA-4/6 activation domains may then interact with chromatin remodeling complexes and histone acetylase complexes to decondense the chromatin of the 120-bp Alb1 enhancer, allowing the observed subsequent binding of four additional transcription factors in the nascent liver bud that develops later.