Epigenetic control: slow and global, nimble and local: Figure 1.

Abstract

The regulation of gene expression involves multiple levels of control, from those that are inheritable to those that are highly responsive to environmental changes. In this issue of Genes & Development, Dong and colleagues (pp. 1159-1173) demonstrate that the dynamically controlled immune response transcription factor NF-B may, in fact, have a role in regulating heterochromatin and gene expression at large distances from its actual target sequences and genes.How the cell regulates the use of its genetic information has been a primary focus of molecular biological research from its inception more than 50 years ago. Two general mechanisms have framed our understanding of how and when the information contained within the DNA is "read" by the cell: those that impede access to the DNA sequence via nucleosome-mediated packaging or DNA methylation, and those mediated by sequence-specific DNA-binding proteins that recruit transcriptional machinery to promoters to activate gene expression. The genome organization into discrete euchromatic and heterochromatic regions (particularly at centromeres, telomeres, and other discrete loci) suggested early on that this packaging was relatively stable and could thereby be inherited to play a key role in development. On the other hand, sequence-specific binding proteins were thought to mediate more nimble, gene-specific control in response to rapidly changing cellular environments. Over the past decade, post-translational modifications of histone tails have emerged as the central regulation step in both types of control, operating at different spatial/temporal scales: the "global" scale that regulates portions of a chromosome at sub-cell cycle time scales, and the "local" scale regulating single transcription units to satisfy dynamically changing physiological needs. However, in this issue of Genes & Development, Dong et al. (2008) provide evidence that suggests a provocative connection between a dynamically regulated transcription factor capable of activating specific target genes, and nonlocal control of gene repression. Heterochromatin: global controlThe term "epigenetics" was coined by Conrad Waddington (Waddington 1942) to account for mechanisms by which genetic information is selectively used as cells differentiate into more specialized functions. The concept of an epigenetic landscape is predicated on the idea that repressive chromatin compaction leads to deselection of genetic information. This pattern is inherited, leading to progressive restriction of cell fate and resulting in differentiation and development. The characteristic chromatin compaction pattern of Drosophila interphase salivary gland chromosomes-where euchromatic and heterochromatic regions are easily distinguished in the microscope-provided an early visual correlate to the accessible and inaccessible genetic loci. This type of epigenetic regulation encompasses multiple genes, is cell type-specific, and relatively stable-less stable than genetic information itself, but more stable than the cellular regulation ...

Dissecting the Regulatory Strategies of NF-κB RelA Target Genes in the Inflammatory Response Reveals Differential Transactivation Logics

“…That is remarkable given that S276 was reported to play critical roles in recruiting CBP/p300 (Zhong et al, 1998), and knockin mutant mice harboring the S276A mutation showed striking animal phenotypes and alterations in the expression of many genes, including some known NF-kB target genes (Dong et al, 2008). Our analysis suggests that these mechanisms are insufficient for TNFinduced NF-kB target gene activation and may support the notion that the phenotype of S276 mutation may be due to alterations at larger time and epigenetic scales (Cheng et al, 2008).…”

Presenilin Controls CBP Levels in the Adult Drosophila Central Nervous System

“…One function of CBP that is critical to an active cell is the histone acetyl-transferase (HAT) function that modifies nucleosomes, presumably so that they can be more easily displaced by the transcription machinery. Therefore, the HAT activity of CBP could influence the acetylation of a few nucleosomes at key gene targets such as those that contain CREB response elements (CREs) for CREB-regulated transcription [27] , or it might have global effects on chromatin structure throughout the genome [28] .…”

New insights into NF-κB regulation and function

“…Thus, unphosphorylated nuclear RelA can affect the expression of genes not directly regulated by NF-κB via epigenetic mechanisms. It is not clear whether this reflects a normal function for wild-type RelA in heterochromatin regulation [51]. Analysis of MEFs from RelA S276A knock-in mice confirmed the previous finding that S276 phosphorylation controls RelA association with CBP, but showed that this is important for expression of only a subset of NF-κB–regulated genes [50].…”