Regulation by Transcription Factors The expression of genes is regulated by DNA-binding proteins that activate or repress transcription. The number of DNA sequences and transcription factors that regulate transcription is much greater than originally anticipated. Most genes contain at least 15–20 discrete regulatory elements within 300 bp of the transcription start site. This densely packed promoter region often contains binding sites for ubiquitous transcription fac tors. However, factors involved in cell-specific expression may also bind to these sequences. Key regulatory elements may also reside at a large distance from the proximal promoter. The globin and the immunoglobulin genes, for example, contain locus control regions that are several kilobases away from the structural sequences of the gene. Specific groups of transcription factors that bind to these promoter and enhancer sequences provide a combinatorial code for regulating transcription. In this manner, relatively ubiquitous factors interact with more restricted factors to allow each gene to be expressed and regulated in a unique manner that is dependent on developmental state, cell type, and numerous extracellular stimuli. Regulatory factors also bind within the gene itself, particularly in the intronic regions. The transcription factors that bind to DNA represent only the first level of regulatory control. Other proteins—co-activators and co-repressors— interact with the DNA-binding transcription factors to generate large regulatory complexes. These complexes are subject to control by numerous cell-signaling pathways and enzymes, leading to phosphorylation, acetylation, sumoylation, and ubiquitination. Ultimately, the recruited transcription factors interact with, and stabilize, components of the basal transcription complex that assembles at the site of the TATA box and initiator region. This basal transcription factor complex consists of >30 different proteins. Gene transcription occurs when RNA polymerase begins to synthesize RNA from the DNA template. A large number of identified genetic diseases involve transcription factors (Table 1).

Table1. Selected Examples of Diseases Caused by Mutations and Rearrangements in Transcription Factors

The field of functional genomics is based on the concept that understanding alterations of gene expression under various physiologic and pathologic conditions provides insight into the underlying functional role of the gene. The ENCODE (Encyclopedia of DNA Elements) project aims at identifying and annotating all functional sequences in the human genome. By revealing specific gene expression profiles, this knowledge can be of diagnostic and therapeutic relevance. The large-scale study of expression profiles is referred to as transcriptomics because the complement of mRNAs transcribed by the cellular genome is called the transcriptome.

Most studies of gene expression have focused on the regulatory DNA elements of genes that control transcription. However, it must be emphasized that gene expression requires a series of steps, including mRNA processing, protein translation, and posttranslational modifications, all of which are actively regulated (Fig. 1).

Fig1. Flow of genetic information. Multiple extracellular signals activate intracellular signal cascades that result in altered regulation of gene expression through the interaction of transcription factors with regulatory regions of genes. RNA polymerase transcribes DNA into RNA that is processed to mRNA by excision of intronic sequences. The mRNA is translated into a polypeptide chain to form the mature protein after undergoing posttranslational processing. CBP, CREB-binding protein; CoA, co-activator; COOH, carboxyterminus; CRE, cyclic AMP responsive element; CREB, cyclic AMP response element–binding protein; GTF, general transcription factors; HAT, histone acetyl transferase; NH2, aminoterminus; RE, response element; TAF, TBP-associated factors; TATA, TATA box; TBP, TATA-binding protein.

Epigenetic Regulation of Gene Expression Epigenetics describes mechanisms and phenotypic changes that are not a result of variation in the primary DNA nucleotide sequence but are caused by secondary modifications of DNA or histones. These modifications include heritable changes such as X-inactivation and imprinting, but they can also result from dynamic posttranslational protein modifications in response to environmental influences such as diet, age, or drugs. The epigenetic modifications result in altered expression of individual genes or chromosomal loci encompassing multiple genes. The term epigenome describes the constellation of covalent modifications of DNA and histones that impact chromatin structure, as well as noncoding transcripts that modulate the transcriptional activity of DNA. Although the primary DNA sequence is usually identical in all cells of an organism, sex- and tissue-specific changes in the epigenome contribute to determining the transcriptional signature of a cell (transcriptome) and hence the protein expression profile (proteome).

Mechanistically, DNA and histone modifications can result in the activation or silencing of gene expression (Fig. 2). DNA methylation involves the addition of a methyl group to cytosine residues. This is usually restricted to cytosines of CpG dinucleotides, which are abundant throughout the genome. Methylation of these dinucleotides is thought to represent a defense mechanism that minimizes the expression of sequences that have been incorporated into the genome such as retroviral sequences. CpG dinucleotides also exist in so-called CpG islands, stretches of DNA characterized by a high CG content, which are found in the majority of human gene promoters. CpG islands in promoter regions are typically unmethylated, and the lack of methylation facilitates transcription.

Fig2. Epigenetic modifications of DNA and histones. Methylation of cytosine residues is associated with gene silencing. Methylation of certain genomic regions is inherited (imprinting), and it is involved in the silencing of one of the two X chromosomes in females (X-inactivation). Alterations in methylation can also be acquired, e.g., in cancer cells. Covalent posttranslational modifications of histones play an important role in altering DNA accessibility and chromatin structure and hence in regulating transcription. Histones can be reversibly modified in their amino terminal tails, which protrude from the nucleosome core particle, by acetylation of lysine, phosphorylation of serine, methylation of lysine and arginine residues, and sumoylation. Acetylation of histones by histone acetylases (HATs), e.g., leads to unwinding of chromatin and accessibility to transcription factors. Conversely, deacetylation by histone deacetylases (HDACs) results in a compact chromatin structure and silencing of transcription.

Histone methylation involves the addition of a methyl group to lysine residues in histone proteins (Fig. 2). Depending on the specific lysine residue being methylated, this alters chromatin configuration, making it either more open or tightly packed. Acetylation of histone proteins is another well-characterized mechanism that results in an open chromatin configuration, which favors active transcription. Acetylation is generally more dynamic than methylation, and many transcriptional activation complexes have histone acetylase activity, whereas repressor complexes often contain deacetylases and remove acetyl groups from histones. Other histone modifications include, among others, phosphorylation and sumoylation.

Furthermore, noncoding RNAs and RNA regulatory networks that bind to DNA have a significant impact on transcriptional activity.

Physiologically, epigenetic mechanisms play an important role in several instances. For example, X-inactivation refers to the relative silencing of one of the two X chromosome copies present in females. The inactivation process is a form of dosage compensation such that females (XX) do not generally express twice as many X-chromosomal gene products as males (XY). In a given cell, the choice of which chromo some is inactivated occurs randomly in humans. But once the maternal or paternal X chromosome is inactivated, it will remain inactive, and this information is transmitted with each cell division. The X-inactive specific transcript (Xist) gene encodes a long non-coding RNA (lncRNA) that mediates gene silencing on one of the X chromosomes. The inactive X chromosome is highly methylated and has low levels of histone acetylation. While the majority of X-chromosomal genes are silenced by X-inactivation, ~15% escape inactivation and are expressed.

Epigenetic gene inactivation also occurs on selected chromosomal regions of autosomes, a phenomenon referred to as genomic imprinting. Through this mechanism, a small subset of genes is only expressed in a monoallelic fashion. Imprinting is heritable and leads to the preferential expression of one of the parental alleles, which deviates from the usual biallelic expression seen for the majority of genes. Remarkably, imprinting can be limited to a subset of tissues. Imprinting is mediated through DNA methylation of one of the alleles. The epigenetic marks on imprinted genes are maintained throughout life, but during zygote formation, they are activated or inactivated in a sex-specific manner (imprint reset) (Fig. 3), which allows a differential expression pattern in the fertilized egg and the sub sequent mitotic divisions. Appropriate expression of imprinted genes is important for normal development and cellular functions. Imprinting defects and uniparental disomy, which is the inheritance of two chromosomes or chromosomal regions from the same parent, are the cause of several developmental disorders such as Beckwith-Wiedemann syn drome, Silver-Russell syndrome, Angelman’s syndrome, and Prader Willi syndrome (see below). Monoallelic loss-of-function mutations in the GNAS1 gene lead to Albright’s hereditary osteodystrophy (AHO). Paternal transmission of GNAS1 mutations leads to an isolated AHO phenotype (pseudopseudohypoparathyroidism), whereas maternal transmission leads to AHO in combination with hormone resistance to parathyroid hormone, thyrotropin, and gonadotropins (pseudohypoparathyroidism type IA). These phenotypic differences are explained by tissue-specific imprinting of the GNAS1 gene, which is expressed primarily from the maternal allele in the thyroid, gonadotropes, and the proximal renal tubule. In most other tissues, the GNAS1 gene is expressed biallelically. In patients with isolated renal resistance to parathyroid hormone (pseudohypoparathyroidism type IB), defective imprinting of the GNAS1 gene results in decreased Gs α expression in the proximal renal tubules. Rett syndrome is an X-linked dominant disorder resulting in developmental regression and stereotypic hand movements in affected girls. It is caused by mutations in the MECP2 gene, which encodes a methyl-binding protein. The ensuing aberrant methylation results in abnormal gene expression in neurons, which are otherwise normally developed.

Fig3. A few genomic regions are imprinted in a parent-specific fashion. The unmethylated chromosomal regions are actively expressed, whereas the methylated regions are silenced. In the germline, the imprint is reset in a parent-specific fashion: both chromosomes are unmethylated in the maternal (mat) germline and methylated in the paternal (pat) germline. In the zygote, the resulting imprinting pattern is identical with the pattern in the somatic cells of the parents.

Remarkably, epigenetic differences also occur among monozygotic twins. Although twins are epigenetically indistinguishable during the early years of life, older monozygotic twins exhibit differences in the overall content and genomic distribution of DNA methylation and histone acetylation, which would be expected to alter gene expression in various tissues.

In cancer, the epigenome is characterized by simultaneous losses and gains of DNA methylation in different genomic regions, as well as repressive histone modifications. Hyper- and hypomethylation are associated with mutations in genes that control DNA methylation. Hypomethylation is thought to remove normal control mechanisms that prevent expression of repressed DNA regions. It is also associated with genomic instability. Hypermethylation, in contrast, results in the silencing of CpG islands in promoter regions of genes, including tumor-suppressor genes. Epigenetic alterations are more easily reversible compared to genetic changes; modification of the epigenome with demethylating agents and histone deacetylases is being used in the treatment of various malignancies.

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مواضيع ذات صلة

Origins and Types of Mutations

The Human Genome

The Polymerase Chain Reaction (PCR)

Additional Nonhistone Proteins Regulate Transcription and Replication

Nonhistone Proteins Organize Long Chromatin Loops

Modifications of Histone Tails Control Chromatin Condensation and Function

Chromatin Exists in Extended and Condensed Forms

Fetal DNA Sequencing and Fetal Genome Analysis

Globin Gene Clusters

Molecular Analysis of Nucleic Acid Sequences

Genes and Genome Complexity

Structure of Nucleic Acids