Even though virtually all cells in the body have the same genetic composition, differentiated cells have distinct structures and functions that arise as a result of lineage specific gene expression programs. Such cell type–specific differences in transcription and translation depend on epigenetic factors (literally, factors that are “above genetics”) that can be conceptualized as follows (Fig. 1):

• Histones and histone-modifying factors. Nucleosomes consist of DNA segments 147 bp long that are wrapped around a central core structure of highly conserved low molecular weight proteins called histones. The resulting DNA-histone complex resembles a series of beads joined by short DNA linkers. The naked DNA of a single human cell is about 1.8 m long. By winding around histones, like spools of thread, the entire genome can be packed into a nucleus as small as 7 to 8 µm in diameter. In most cases, this structured DNA, termed chromatin, is not wound uniformly. Thus at the light microscopic level, nuclear chromatin is recognizable as cytochemically dense and transcriptionally inactive heterochromatin and disperse, transcriptionally active euchromatin (see Fig. 2). In general, only the regions that are “unwound” are available for transcription. Chromatin structure can therefore regulate transcription independent of traditional promoters and DNA-binding elements and, due to variations between cell types, helps to define cellular identity and activity.

Fig1. Histone organization. (A) Nucleosomes are comprised of octamers of histone proteins (two each of histone subunits H2A, H2B, H3, and H4) encircled by 1.8 147 bp DNA loops. Histones sit on 20- to 80-nucleotide stretches of linker DNA between nucleosomes. Histone subunits are positively charged, thus allowing compaction of negatively charged DNA. (B) The relative state of DNA unwinding (and thus access for transcription factors) is regulated by histone modification, including acetylation, methylation, and/or phosphorylation; these “marks” are dynamically written and erased. Certain marks such as histone acetylation “open up” the chromatin structure, whereas others such as methylation of particular histone residues condense DNA to silence genes. DNA can also be methylated, leading to transcriptional inactivation.

Fig2. The organization of nuclear DNA. At the light microscopic level, the nuclear genetic material is organized into dispersed, transcriptionally active euchromatin and densely packed, transcriptionally inactive heterochromatin; chromatin can also be mechanically connected with the nuclear membrane, and membrane perturbation can thus influence transcription. Chromosomes (as shown) can be visualized only during mitosis. During mitosis, they are organized into paired chromatids connected at centromeres; the centromeres act as the locus for the formation of a kinetochore protein complex that regulates chromosome segregation at metaphase. The telomeres are repetitive nucleotide sequences that cap the termini of chromatids and permit repeated chromosomal replication without deterioration of genes near the ends. The chromatids are organized into short “P” (“petite”) and long “Q” (next letter in the alphabet) arms. The characteristic banding pattern of chromatids has been attributed to relative GC content (less GC content in bands relative to interbands), with genes tending to localize to interband regions. Individual chromatin fibers are comprised of a string of nucleosomes— DNA wound around octameric histone cores—with the nucleosomes connected via DNA linkers. Promoters are noncoding regions of DNA that initiate gene transcription; they are on the same strand and upstream of their associated gene. Enhancers can modulate gene expression over distances of 100 kb or more by looping back onto promoters and recruiting additional factors that drive the expression of pre–messenger RNA (mRNA) species. Intronic sequences are spliced out of the pre-mRNA to produce the final message that is translated into protein—without the 3′–untranslated region (UTR) and 5′-UTR. In addition to the enhancer, promoter, and UTR sequences, noncoding elements, including short repeats, regulatory factor binding regions, noncoding regulatory RNAs, and transposons, are distributed throughout the genome.

Histones are not static, but rather are highly dynamic structures regulated by a host of nuclear proteins. Thus chromatin remodeling complexes can reposition nucleosomes on DNA, exposing (or obscuring) gene regulatory elements such as promoters. “Chromatin writer” complexes, on the other hand, carry out over 70 different histone modifications generically denoted as “marks.” Such covalent alterations include methylation, acetylation, or phosphorylation of specific amino acids within histones.

Actively transcribed genes in euchromatin are associated with histone marks that make the DNA accessible to RNA polymerases. In contrast, inactive genes have histone marks that enable DNA compaction into hetero chromatin. Histone marks are reversible through the activity of “chromatin erasers.” Still other proteins function as “chromatin readers,” binding histones that bear particular marks and thereby regulating gene expression.

• Histone methylation. Both lysines and arginines can be methylated by specific writer enzymes; methylation of histone lysine residues can lead to transcriptional activation or repression, depending on which histone residue is marked.

• Histone acetylation. Lysine residues are acetylated by histone acetyltransferases (HATs), whose modifications tend to open the chromatin and increase transcription. In turn, these changes can be reversed by histone deacetylases (HDACs), leading to chromatin condensation.

• Histone phosphorylation. Serine residues can be modified by phosphorylation; depending on the specific residue, the DNA may be opened for transcription or condensed and inactive.

• DNA methylation. High levels of DNA methylation in gene regulatory elements typically result in transcriptional silencing. Like histone modifications, DNA methylation is tightly regulated by methyltransferases, demethylating enzymes, and methylated-DNA-binding proteins.

• Chromatin organizing factors. Much less is known about these proteins, which are believed to bind to noncoding regions and control long-range looping of DNA, thus regulating the spatial relationships between enhancers and promoters that control gene expression.

Deciphering the mechanisms that allow epigenetic factors to control genomic organization and gene expression in a cell-type-specific fashion is an extraordinarily complex proposition. Despite the intricacies, there is already ample evidence that dysregulation of the “epigenome” has a central role in malignancy, and emerging data indicate that many other diseases are associated with inherited or acquired epigenetic alterations. Unlike genetic changes, many epigenetic alterations (e.g., histone acetylation and DNA methylation) are reversible and amenable to therapeutic intervention; HDAC and DNA methylation inhibitors are already being tested in the treatment of various forms of cancer.

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مواضيع ذات صلة

Micro-RNA and Long Noncoding RNA

Noncoding DNA

DNA Synthesis Occurs During the S Phase of the Cell Cycle

Formation of Replication Bubbles

Initiation & Elongation of DNA Synthesis

The Exact Function of Much of the Mammalian Genome is Not Well Understood

DNA is organized into Chromosomes

Some Regions of Chromatin are “Active” & Others are “Inactive”

The Nucleosome Contains Histone & DNA

Histones Are the Most Abundant Chromatin Proteins

Specific Nucleases Digest Nucleic Acids

Directions for Future Research in Molecular Biology