Chromatin structure provides an additional level of control of gene transcription. As discussed in Chapter 35, large regions of chromatin are transcriptionally inactive while others are either active or potentially active. With few exceptions, each cell contains the same complement of genes; hence, the development of specialized organs, tissues, and cells, and their function in the intact organism depend on the differential expression of genes.

Some of this differential expression is achieved by having different regions of chromatin available for transcription in cells from various tissues. For example, the DNA containing the β-globin gene cluster is in “active” chromatin in the reticulocyte but in “inactive” chromatin in muscle cells. All the fac tors involved in the determination of active chromatin have not been elucidated. The presence of nucleosomes and of complexes of histones and DNA certainly provides a barrier against the ready association of most transcription factors with specific DNA regions. The dynamics of the formation and disruption of nucleosome structure are therefore an important part of eukaryotic gene regulation.

Histone covalent modification, also dubbed the histone code, is an important determinant of gene activity. Histones are subjected to a wide range of specific posttranslational modifications. These modifications are dynamic and reversible. Histone acetylation and deacetylation are best understood. The surprising discovery that histone acetylase and other enzymatic activities are associated with the coregulators involved in regulation of gene transcription has provided a new concept of gene regulation. Acetylation is known to occur on lysine residues in the amino terminal tails of histone molecules, and has been consistently correlated with either active transcription, or alternatively, transcriptional potential. Histone acetylation reduces the positive charge of these tails and likely contributes to a decrease in the binding affinity of histones for the negatively charged DNA. Moreover, such covalent modification of the histones creates new binding, or docking sites for additional proteins such as ATP-dependent chroma tin remodeling complexes that contain subunits that carry structural domains that specifically bind to histones that have been subjected to coregulator-deposited PTMs. These complexes can increase accessibility of adjacent DNA sequences by removing or otherwise altering nucleosomal histones. Together then coregulators (chromatin modifiers and chro matin remodelers), working in conjunction, can “open up” gene promoters and regulatory regions, facilitating binding of other trans-factors such as transcriptional activator proteins, RNA polymerase II and the GTFs. Histone deacetylation catalyzed by transcriptional corepressors would have the opposite effect. Different proteins with specific acetylase and deacetylase activities are associated with various components of the transcription apparatus. The proteins that catalyze histone PTMs are sometimes referred to as “code writers” while the proteins that recognize, bind, and thus interpret these histone PTMs are termed “code readers” while the enzymes that remove histone PTMs are called “code erasers.” (The analogy to signal transduction, with its kinases, phosphatases, and phospho-amino acid binding proteins should be apparent—see Chapter 42.) Collectively then, histone PTMs represent a very dynamic, potentially information-rich source of regulatory information. The exact rules and mechanisms defining the specificity of these various processes are under investigation. Some specific examples are illustrated in Chapter 42. A variety of commercial enterprises are working to develop drugs that specifically alter the activity of the proteins that orchestrate the presence and composition of the his tone code, whose relevant PTMs continue to grow at a rapid pace.

DNA-mediated reactions, the methylation of deoxycytidine residues, 5meC, (in the sequence 5′-meCpG-3′) in DNA has important effects on chromatin, some of which lead to a decrease in gene transcription. For example, in mouse liver, only the unmethylated ribosomal RNA encoding genes can be expressed, and there is evidence that many animal viruses are not transcribed when their DNA is methylated. Acute demethylation of 5meC residues in specific regions of steroid hormone inducible genes has been associated with an increased rate of transcription of the gene. However, as with many histone PTMs, it is not yet possible to generalize that methylated DNA is transcriptionally inactive, that all inactive chromatin is methylated, or that active DNA is not methylated.

Finally, the binding of specific transcription factors to cognate DNA elements may result in disruption of nucleosomal structure. Most eukaryotic genes have multiple protein binding DNA elements. The serial binding of transcription factors to these elements—in a combinatorial fashion—may either directly disrupt the structure of the nucleosome, pre vent its reformation, or recruit, via protein–protein interactions, multiprotein coregulator complexes that have the ability to covalently modify and/or remodel nucleosomes. These reactions result in chromatin-level structural changes that in the end increase or decrease DNA accessibility to other factors and the transcription machinery.

Eukaryotic DNA that is in an “active” region of chroma tin can be transcribed. As in prokaryotic cells, a promoter dictates where the RNA polymerase will initiate transcription, but the promoter in mammalian cells is more complex. Additional complexity is added by elements or factors that enhance or repress transcription, define tissue specific expression, and modulate the actions of many effector molecules. Finally, recent results suggest that gene activation and repression might occur when particular genes move into or out of different subnuclear compartments or locations wherein variable amounts of transcription proteins and RNA either promote or disrupt biomolecular condensate formation that stimulate or inhibit transcription.

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مواضيع ذات صلة

Epigenetic Mechanisms Contribute Importantly to the Control of Gene Transcription

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