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A novel role for TAF4 in post-natal hepatocyte maturation

Upper panel: Section through a normal liver. The cell membranes are well delimited (in green) and normal bile ducts (BD) are formed.
Lower panel: Section through a liver lacking TAF4. The cell membranes are less well delimited (in green), and the bile ducts are defective (dBDs) and do not form a proper lumen to drain the bile from the liver.

TAF4, a subunit of transcription factor II D, directs promoter occupancy of nuclear receptor HNF4A during post-natal hepatocyte differentiation.

Alpern D(1), Langer D(1), Ballester B(2), Le Gras S(1), Romier C(3), Mengus G(1), Davidson I(1).

Elife Sept. 10, 2014

Oct. 3, 2014

The group of Irwin Davidson have discovered a novel role for the TAF4 protein in hepatocyte maturation opening the way to understanding its eventual role in diabetes. The results are published by Alpern et al., on 3 October in eLife.


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.


The group of Irwin Davidson has studied these proteins for several years, however understanding their function is complex as removing them from the cell is often lethal. As loss of TAF4 results in lethality at the embryonic stage, the group have have now studied the function of TAF4 by removing it from liver hepatocytes just after birth. At birth, the liver undergoes a radical transformation when the genes required for adult metabolism are switched on and the embryonic genes are switched off. This change corresponds to the need of the animal to feed itself after birth. Loss of TAF4 at this stage causes severe hypoglycaemia, leading to death between 10-15 days after birth and disorganisation of the liver. In liver cells lacking TAF4, some 1,408 genes that are normally turned on just after birth and that are necessary for the metabolic functions of the liver are not properly switched on, whereas 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 copying of the DNA sequence into 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 interacts directly with a protein called HNF4A, which is known to be important in the development of the liver and in controlling metabolism. Through this interaction TAF4 directs HNF4A to interact with over 7,000 important DNA sequences many of which are necessary to switch on the metabolic genes. Mutations in HNF4A are responsible for a syndrome known as Maturity Onset of Diabetes in the Young (MODY). The group will now ask whether these mutations affect interaction of HNF4A with TAF4 and hence whether altering this interaction contributes to this form of diabetes.

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