RESUMEN
Epigenetic mechanisms including the post-translational modifications of histones, incorporation of histonevariants and DNA methylation have been suggested to play an important role in genome plasticity by allowingthe cellular environment to define gene expression and the phenotype of an organism. Studies over the pastdecade have elucidated how these epigenetic mechanisms are significant in orchestrating various biologicalprocesses and contribute to different pathophysiological states. However, the role of histone isoforms and theirimpact on different phenotypes and physiological processes associated with diseases are not fully clear. Thisreview is focussed on the recent advances in our understanding of the complexity of eukaryotic H2A isoformsand their roles in defining nucleosome organization. We elaborate on their potential roles in genomic complexity and regulation of gene expression, and thereby on their overall contribution towards cellular phenotypeand development of diseases
RESUMEN
Besides the fundamental components of the chromatin, DNA and octameric histone, the non-histone chromatinproteins and non-coding RNA play a critical role in the organization of functional chromatin domains. Thenon-histone chromatin proteins therefore regulate the transcriptional outcome in both physiological andpathophysiological state as well. They also help to maintain the epigenetic state of the genome indirectly.Several transcription factors and histone interacting factors also contribute in the maintenance of the epigeneticstates, especially acetylation by the induction of autoacetylation ability of p300/CBP. Alterations of KATactivity have been found to be causally related to disease manifestation, and thus could be potential therapeutictarget.
RESUMEN
The special AT-rich DNA-binding protein 1 (SATB1) is a matrix attachment region (MAR)-binding protein that acts as a global repressor via recruitment of CtBP1:HDAC1-containing co-repressors to its binding targets. The N-terminal PSD95/Dlg-A/ZO-1 (PDZ)-like domain of SATB1 mediates interactions with several chromatin proteins. In the present study, we set out to address whether the PDZ-domain-mediated interactions of SATB1 are critical for its in vivo function as a global repressor. We reasoned that since the N-terminal PDZ-like domain (amino acid residues 1–204) lacks DNA binding activity, it would fail to recruit the interacting partners of SATB1 to its genomic binding sites and hence would not repress the SATB1-regulated genes. Indeed, in vivo MAR-linked luciferase reporter assay revealed that overexpression of the PDZ-like domain resulted in de-repression, indicating that the PDZ-like domain exerts a dominant negative effect on genes regulated by SATB1. Next, we developed a stable dominant negative model in human embryonic kidney (HEK) 293T cells that conditionally expressed the N-terminal 1–204 region harbouring the PDZ-like domain of SATB1. To monitor the effect of sequestration of the interaction partners on the global gene regulation by SATB1, transcripts from the induced and uninduced clones were subjected to gene expression profiling. Clustering of expression data revealed that 600 out of 19000 genes analysed were significantly upregulated upon overexpression of the PDZ-like domain. Induced genes were found to be involved in important signalling cascades and cellular functions. These studies clearly demonstrated the role of PDZ domain of SATB1 in global gene regulation presumably through its interaction with other cellular proteins.