Research work · 2014
Decision letter: TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation
Abstract
To decode the information contained within a gene, a number of processes need to occur. For example, the DNA sequence that makes up the gene needs to be copied to make a molecule of RNA, which is then translated to build the corresponding protein. The first steps in the manufacture of RNA involve a structure called a ‘pre-initiation complex’ moving an enzyme called RNA polymerase II to the start of the gene that needs to be copied. The pre-initiation complex is made up of many types of protein, including a set of proteins called TAFs. However, the way that these proteins work in mammals is not well understood. There are good reasons for this: proteins are often studied by seeing what happens when the protein is removed, but many TAFs are so important that removing them is lethal. Alpern et al. have now studied the function of TAF4 by removing this protein from mouse liver cells. This causes severe hypoglycemia (that is, a drop in sugar levels in the blood). Moreover, it seems as if these cells start dying before they become fully mature. In liver cells lacking TAF4, some 1408 genes that are normally turned on just after birth are not properly switched on; these genes are necessary for the metabolic functions of the liver. Furthermore, 776 genes that are normally turned off after birth continue to be expressed. It seems that the absence of TAF4 sometimes disrupts the formation of the pre-initiation complex, which would slow down the production of RNA. However, it can also have the opposite effect by increasing the activity of RNA polymerase II, hence making too many copies of RNA from some genes. Alpern et al. also find that TAF4 is needed to allow a protein called HNF4A, which is important in the development of the liver and in controlling metabolism, to interact with over 7000 important DNA sequences. Mutations in HNF4A are responsible for a syndrome known as Maturity Onset of Diabetes in the Young. The next stage in this work will be to explore if these mutations influence the interaction between HNF4A and TAF4, and if they do, whether these changes contribute to this form of diabetes.