On p300, enhancers and neurodevelopmental disorders.

The P300 or adenovirus E1A-associated cellular p300 transcriptional co-activator protein, is a transcriptional regulator (1, 2). It harbours an intrinsic acetyltransferase activity. Thus, by definition it affects gene transcription by inducing chromatin remodelling close to promoter sites and by providing chromatin accessibility to transcription factors and the transcriptional machinery (1). Moreover, P300 can interact with all four histone types of the nucleosome core i.e., H2A, H2B, H3 and H4 (2). Depending on the context of interactions with its co-regulators, gene transcription can either be upregulated  or downregulated, like in the case of p53 and ACTR respectively (3). By specifically interacting with the phosphorylated form of CREB, it also affects cAMP-gene regulation. Furthermore, the P300 protein has a critical role in embryonic development and neuraldevelopment. This is evident in humans, in the case of p300 mutations that cause loss of function and/or copy number alteration (reductions in copy number). These mutations cause an embryo to develop a condition called, broad thumb-hallux syndrome. Some of the phenotypic features of this syndrome, is craniofacial and limb formation abnormalities and mental retardation, highlighting the importance of p300 function during morphogenesis and neuraldevelopment in humans. The massive amount of genes under P300 control during these critical stages of embryonic development was revealed when Visel et al. (2009)(4), examined P300 binding sites by chromatin immunoprecipitation coupled to parallel massive sequencing (Chip-seq) in mouse embryos. Specifically the authors examined, P300 binding sites, in mouse embryos of embryonic age 11.5 (E11.5). This is an important stage for especially for neuraldevelopment, since in the mouse embryo, this is the stage were the neocortex epithelium initiates to expand by increasing proliferative divisions of radial glia cells (neural progenitors). Binding sites where examined in the forebrain (includes both the neocortex and the ventral telencephalon), the limbs and the midbrain. The sample size was more than 150 (!!!) embryos per tissue. In this case P300 binding was used to predict enhancer areas, since P300 was shown to associate in vitro with enhancer areas.Enhancers are DNA regions which enhance the transcription of a gene. Just for the forebrain, 2,543 P300 binding sites were identified by Chip-seq. Moreover, to examine the correspondence of binding sites to known genes, the authors performed tissue specific microarrays. In the forebrain’s case, they found that for the 885 genes which are overexpressed in the forebrain, 14 % of the identified P300 binding sites are within 101 kb from the promoter. Moreover, the enrichment for P300 binding sites was observed to increase according to the level of overexpression of forebrain-specific genes. The conclusion by the authors was that mapping P300 binding is a very accurate way to detect enhancers. In a relatively recent review, Williamson et al. (2011), provide information around enhancers and how knowing more about them might be useful to understand human disease. For example, quoting the authors and Noonan and McCallion (2010): “almost half of single nucleotide polymorphisms (SNPs) that show statistical associations with common/complex human disease and quantitative traits in genome-wide association studies (GWAS) are within noncoding regions and gene deserts and thus, potentially involve enhancers“. For the case of neurodevelopmental disorders, such as autism and schizophrenia, gaining more insights on how early imbalances in the brain structure come up though gene expression de-regulation, is critical. Achieving such progress, will help to understand how the disorder evolves and establishes in the brain. Also, this information, can hopefully lead us into finding ways to treat and perhaps prevent the disorder from evolving .

P300 Binding Sites in the mouse heart and (on the left ) conservation in rat, human, dog and elephant, by Hardison R.C., Nature Genetics (2010)

We are still a long way from home. Nevertheless, the rapid advancement of next generation sequencing technology (NGS), coupled with the parallel advancement in the computational methods created to explain sequencing and gene expression data, provide significant insights towards steps of progress.

References
1. Wikipedia>p300-CBP
2. GeneCards>p300
3. Li,Q. et al.(2002), Mol.Endo., 16(12),1819-2827.
4. Visel, A., et al.(2009), Nature 457(12), 854-858.
5. Williamson et al. (2011), Dev.Cell., 21(1), 17-19.
6. Noonan, J.P., and McCallion, A.S. (2010), Annu.Rev. Genomics Hum. Genet., 11, 1–23.
7. Hardison, R.C. (2010), Nature Genetics, 42, 734–735.

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Filed under Biology, Cell Cycle, Gene Expression, Microarray, Neurons, Neuroscience, Science, The Development Series

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