Transcriptional activation can be divided into three main mechanisms: 1. Events that alter chromatin structure can enhance the access of transcription factors to DNA. For example, histone acetylation generally opens chromatin structure and is correlated with transcriptional activation. 2. Posttranslational modifications of transcription factors, such as phosphorylation, can induce the assembly of active transcription complexes. As an example, phosphorylation of CREB protein on serine 133 induces a conformational change that allows the recruitment of CREBbinding protein (CBP), a factor that integrates the actions of many transcription factors, including proteins, with histone acetyltransferase activity. 3. Transcriptional activators can displace a repressor protein. This mechanism is particularly common during development when. | Chapter 062. Principles of Human Genetics Part 8 Transcriptional activation can be divided into three main mechanisms 1. Events that alter chromatin structure can enhance the access of transcription factors to DNA. For example histone acetylation generally opens chromatin structure and is correlated with transcriptional activation. 2. Posttranslational modifications of transcription factors such as phosphorylation can induce the assembly of active transcription complexes. As an example phosphorylation of CREB protein on serine 133 induces a conformational change that allows the recruitment of CREB-binding protein CBP a factor that integrates the actions of many transcription factors including proteins with histone acetyltransferase activity. 3. Transcriptional activators can displace a repressor protein. This mechanism is particularly common during development when the pattern of transcription factor expression changes dynamically. Of course these mechanisms are not mutually exclusive and most genes are activated by some combination of these events. Suppression of gene expression is as important as gene activation in the control of cell differentiation and function. Some mechanisms of repression are the corollary of activation. For example repression is often associated with histone deacetylation or protein dephosphorylation. For nuclear hormone receptors transcriptional silencing involves the recruitment of repression complexes that contain histone deacetylase activity. Aberrant expression of repressor proteins is sometimes associated with neoplasia. The t 15 17 chromosomal translocation that occurs in promyelocytic leukemia fuses the PML gene to a portion of the retinoic acid receptor a RAR a gene Table 62-2 . This event causes unregulated transcriptional repression in a manner that precludes normal cellular differentiation. The addition of the RAR ligand retinoic acid activates the receptor thereby relieving repression and allowing cells to differentiate and .
