The importance of gene transcription for normality
To transcribe the information contained in our genes or to repair the dozens of breaks that occur daily in our DNA, our enzymes must be able to directly access the DNA to perform their functions. However, in the cell nucleus, this access is limited because the DNA strands are often tightly coiled and packed around proteins like threads around spools. Chromatin remodeling through histone acetylation is critical for epigenetic regulation of transcription and has been recently identified as an essential mechanism for our bodily cellular homeostasis and normal cognitive function. Altered levels of global histone acetylation have been observed in several in vivo models of human cancers and neurodegenerative diseases as well; and are thought to be involved in the pathogenesis of various memory related disorders.
TIP60 biolgy and structure
Researchers from Lawrence Berkeley National Laboratory (Berkeley Lab), UC Berkeley, the Institute for Systems Biology, and Université Laval now have a better understanding of the protein complex that creates access to packed DNA, TIP60. Knowing the detailed structure and behavior of TIP60 could provide insight into different diseases where the protein complex plays a role, such various cancers and even Alzheimer disease. Indeed, TIP60 is an histone acetyltransferase (HAT; this is why si also called lysine acetyl-transferase 5 or KAT5) that was also found to associate in neuronal membrane with beta-amyloid precursor (beta-APP) and binding proteins like presenilin and Fe65. In this regard, the HAT Tip60 is a multifunctional enzyme involved in a variety of chromatin-mediated processes that include transcriptional regulation, apoptosis and cell-cycle, with recently reported roles in nervous system function as well.
TIP60 malfunction is associated with several types of cancer, including colon, lung, breast, pancreatic, stomach, and metastatic melanoma. It is also associated with neurological disorders such as Alzheimer’s. Previous work has demonstrated that Tip60 HAT activity is required for nervous system development via the transcriptional control of genes enriched for neuronal function. Tip60 HAT activity controls synaptic plasticity and growth, something which is lost in dementia like Alzheimer disease. The structure of the human TIP60 reveals how evolution has led to the merging of two distinct molecular functions into a single complex, readjusting the way structural modules come together to fit its dual functionality. The researchers were able to study the structure of this complex, which is made up of 17 proteins, and the interactions between its components. They used several approaches, including high-resolution cryo-electron microscopy at the Nogales lab at UC Berkeley.
To shed light on the structure of TIP60, scientists used ultra-purified protein samples. After the analyses wer completed, the researhcers noted that when access to DNA is restricted, the enzymes that repair DNA breaks cannot function, and significant cellular damage can occur. The same problem can occur with tumor suppressor genes like p53. For them to be expressed, TIP60 must be able to create an opening into the DNA. Scientists said that a good understanding of the structure of TIP60 is essential if we hope to develop new targeted therapies for diseases associated with low levels of TIP60, including Alzheimer and other neurodegenerative diseases. The interaction of Tip60 with ataxin 1 protein has been reported to contribute to cerebellar degeneration associated with spinocerebellar ataxia (SCA1), a neurodegenerative disease caused by polyglutamine tract expansion.
Histone epigenetics and brain development
Accumulating evidence shows that hyperacetylation can be fatal to neurons. Under normal conditions, increasing hyperacetylation by treating neurons with a general HDAC inhibitor like trichostatin A has been found to induce neuronal apoptosis. Similarly, increasing acetylation levels by overexpressing the HAT CBP in resting neurons has been reported to enhance chromatin condensation and neuronal death. In order to maintain cellular homeostasis, HAT/HDAC equilibrium and therefore histone acetylation is strictly regulated as it is essential to maintain the functional status of neurons. Based on these findings, it is speculated that overexpression of Tip60 disrupts the acetylation balance, thus skewing the neuronal survival pathway towards apoptosis and ultimately cell death. In support of this concept, altered levels of global histone acetylation have been observed in many in vivo models of neurodegenerative diseases
Parkinson’s, Huntington’s and Alzheimer’s disease: these diseases are also characterized by neuronal cell death that increases over time and underlies an array of symptoms that depend on the function of the lost neuronal population. It has been proposed that in AD, in addition to the deposition of toxic β-amyloid plaques in the brain, neurodegeneration may also be caused via γ-secretase cleavage of b-APP that generates carboxy-terminal fragments that are toxic to neurons. One of these is the famous beta-amyloid peptide 1-42. Interestingly, APP C-terminal domain induced apoptosis has previously been reported to be mediated via Tip60 HAT activity in vitro. In this study, nervous system specific co-expression of APP and Tip60 defective mutant increases apoptosis, while overexpression of wild-type Tip60 with APP counteracts this effect; and that these phenotypes are dependent upon the Tip60 interacting C-terminus of APP.
Importantly, this finding, in conjunction with previously published reports supporting a causative role for Tip60 in the control of synaptic plasticity and the transcriptional regulation of genes enriched for neuronal function, support the concept that misregulation of Tip60 enzymatic activity can lead to aberrant gene expression within the nervous system that contributes to the AD associated neurodegenerative process. Epigenetic regulation has been postulated to provide a coordinated system of regulating gene expression at each stage of neurogenesis, thus promoting brain and CNS development, neural plasticity, learning and memory. The identification of a number of neurological disorders that result from HAT misregulation underscores a crucial role for acetylation in proper CNS development. For example, missense mutations in the CBP and p300 genes cause Rubinstein-Taybi syndrome.
In this human disease vhilren display complex phenotypic abnormalities including short stature, learning difficulties and the future development of cancer. Since histone epigenetics have also been observed in embryonal neurogenesis, this open the possibility to predict if people are effectively having their “root “ to develop dementia in the future.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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