The molecules and regulatory biology described earlier con tributes importantly to transcriptional regulation. Indeed, in recent years the role of covalent modification of DNA and histone (and nonhistone) proteins and the newly discovered ncRNAs has received tremendous attention in the field of gene regulation research, particularly through investigation into how such chemical modifications and/or molecules stably alter gene expression patterns without altering the underlying DNA gene sequence. This field of study has been termed epigenetics. As mentioned in Chapter 35, one aspect of these mechanisms, PTMs of histones has been dubbed the histone codeor histone epigenetic code. The term “epigenetics” means “above genetics” and refers to the fact that these regulatory mechanisms do not change the underlying regulated DNA sequence, but rather simply the expression patterns, or function, of this DNA. Epigenetic mechanisms play key roles in the establishment, maintenance, and reversibility of transcriptional states. A key feature of epigenetic mechanisms is that the controlled transcriptional on/off states can be maintained through multiple rounds of cell division. This observation indicates that there must be robust, biochemically based mechanisms to maintain and stably propagate these epigenetic states.

Two forms of epigenetic signals, cis- and trans-epigenetic signals, can be described; these are schematically illustrated in Figure 1. A simple trans-signaling event composed of positive transcriptional feedback mediated by an abundant, diffusible transactivator that efficiently partitions roughly equally between mother and daughter cell at each division is depicted in Figure 1A. So long as the indicated, transcription factor is expressed at a sufficient level to allow all subsequent daughter cells to inherit the trans-epigenetic signal (transcription factor), such cells will have the cellular or molecular phenotype dictated by the other target genes of this transcriptional activator. Shown in Figure 1 panel B is an example of how a cis-epigenetic signal (here as a specific meCpG methylation mark) can be stably propagated to the two daughter cells following cell division. The hemi-methylated (ie, only one of the two DNA strands is 5meC-modified) DNA mark generated during DNA replication directs the methylation of the newly replicated strand through the action of ubiquitous maintenance DNA methylases. Thus, the original 5meC methylation mark ultimately results in both DNA daughter strands having the complete cis-epigenetic mark.

Fig1. cis- andtrans-epigenetic signals. (A) An example of an epigenetic signal that acts in trans. A DNA-binding transactivator protein (yellow circle) is transcribed from its cognate gene (yellow bar) located on a particular chromosome (blue). The expressed protein is freely diffusible between nuclear and cytoplasmic compartments. Note that excess transactivator reenters the nucleus following cell division, binds to its own gene, and activates transcription in both daughter cells. This cycle re-establishes the positive feedback loop that was in effect prior to cell division, and thereby enforces stable expression of this transcriptional activator protein in both cells. (B) A cis-epigenetic signal; a gene (pink) located on a particular chromosome (blue) carries a cis-epigenetic signal (small yellow flag) within the regulatory region upstream of the pink gene transcription unit. In this case, the epigenetic signal is associated with active gene transcription and subsequent gene product production (pink circles). During DNA replication, the newly replicated chromatid serves as a template that both elicits, and templates, the introduction of the same epigenetic signal, or mark, on the newly synthesized, unmarked chromatid. Consequently, both daughter cells contain the pink gene in a similarly cis-epigenetically marked state, which ensures expression in an identical fashion in both cells. See text for more detail.

Both cis- and trans-epigenetic signals can result in stable and hereditable expression states, and therefore generally represent type C gene expression responses (ie, Figure 38–1). However, it is important to note that both states can be reversed if either the trans- or cis-epigenetic signals are removed by, for example, extinguishing the expression of the enforcing transcription factor (trans-signal) or by completely removing a DNA cis-epigenetic signal (via DNA demethylation). Enzymes have been described that can remove both protein PTMs and 5^meC modifications.

Stable transmission of epigenetic on/off states can be affected by multiple molecular mechanisms. Shown in Figure 2 are three ways by which cis-epigenetic marks can be propagated through a round of DNA replication. The first example of epi genetic mark transmission involves the propagation of DNA 5meC marks, and occurs as described in Figure 1. The second example of epigenetic state transmission illustrates how a nucleosomal histone PTM (in this example, Lysine K-27 trimethylated histone H3; H3K27me3) can be propagated. In this example immediately following DNA replication, both H3K27me3-marked and H3-unmarked nucleosomes randomly reform on both daughter DNA strands. The polycomb repressive complex 2 (PRC2), composed of EED-SUZ12 EZH2 and RbAP subunits, binds to the nucleosome containing the preexisting H3K27me3 mark via the EED subunit. Binding of PRC2 to this histone mark stimulates the methylase activity of the EZH2 subunit of PRC2, which results in the local methylation of nucleosomal H3. Histone H3 methylation thus causes the full, stable transmission of the H3K27me3 epigenetic mark to both chromatids. Finally, locus/sequence specific targeting of nucleosomal histone epigenetic cis-signals can be attained through the action of lncRNAs as depicted in Figure 2, panel C. Here a specific ncRNA interacts with target DNA sequences and the resulting RNA–DNA complex is recognized by RBP, an RNA-binding protein. Then, likely through a specific adaptor protein (A), the RNA-DNA-RBP complex recruits a chromatin modifying complex (CMC) that locally modifies nucleosomal histones. Again, this mechanism leads to the transmission of a stable epigenetic mark.

Fig2. Mechanisms for the transmission and propagation of epigenetic signals following a round of DNA replication. (A) Propagation of a 5meC signal (yellow flag; see Figure 1B). (B) Propagation of a histone PTM epigenetic signal (H3K27me) that is mediated through the action of the PRC2, a chromatin modifying complex, or CMC. PRC2 is composed of EED, EZH2 histone methylase, RbAP, and SUZ12 subunits. Note that in this context, PRC2 is both a histone code reader (via the methylated histone–binding domain in EED) and histone code writer (via the SET domain histone methylase within EZH2). Location-specific deposition of the histone PTM cis-epigenetic signal is targeted by the recognition of the H3K27me marks in preexisting nucleosomal histones (yellow flag). (C) Another example of the transmission of a histone epigenetic signal (yellow flag) except here signal-targeting is mediated through the action of small ncRNAs that work in concert with an RNA binding protein (RBP), an adaptor (A) protein, and a CMC. See text for more detail. (Reproduced with permission from Bonasio R,Tu S, Reinberg D. Molecular signals of epigenetic states. Science. 2010;330(6004):612-616.)

Additional work will be required to establish the complete molecular details of epigenetic processes, determine how ubiquitously these mechanisms operate, identify the full complement of molecules involved, and genes controlled. Epigenetic signals are critically important to gene regulation as evidenced by the fact that mutations and/or overexpression of many of the molecules that contribute to epigenetic control lead to human disease.

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مواضيع ذات صلة

The Chromatin Template Contributes Importantly to Eukaryotic Gene Transcription Control

The Genetic Switch of Bacteriophage Lambda (λ) Provides Another Paradigm for Understanding the Role of Conditional Regulatory Protein-DNA Interactions in Transcriptional Control in Eukaryotic Cells

Analysis of Lactose Metabolism in E. coli Led to the Discovery of the Basic Principles of Gene Transcription

Biologic Systems Exhibit Three Types of Temporal Responses to a Regulatory Signal

Regulated Expression of Genes is Required for Development, Differentiation, & Adaptation

Posttranslational Processing Affects the Activity of many Proteins

Like Transcription, Protein synthesis can be described in three phases: Initiation, Elongation, & Termination

Mutations result when changes occur in the Nucleotide Sequence

The Genetic Code is Degenerate, Unambiguous, Nonoverlapping, Without Punctuation, & Universal

RNAs can be Extensively Modified

RNA Molecules are Extensively Processed Before They Become Functional

Phosphorylation Activates Pol II