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The Central Dogma and
Epigenetic Regulation of Gene
Expression
DNA and RNA: Structure, Function, and
Biochemical Properties
Structure and Composition
DNA (deoxyribonucleic acid) and RNA (ribonucleic acid) are both nucleic acids that store and transmit genetic information. DNA is a double-stranded molecule, while RNA is typically single- stranded. Both DNA and RNA are composed of nucleotides, which consist of a 5- carbon sugar (deoxyribose in DNA, ribose in RNA), a phosphate group, and one of four nitrogenous bases (adenine, guanine, cytosine, and thymine in DNA; adenine, guanine, cytosine, and uracil in RNA). In DNA, the bases form complementary pairs: adenine (A) pairs with thymine (T), and guanine (G) pairs with cytosine (C). In RNA, uracil (U) replaces thymine and pairs with adenine. The sugar-phosphate backbones of the DNA strands are on the outside of the double helix, while the nitrogenous bases are stacked in the interior, forming the core of the structure.
The Central Dogma of Biology
The central dogma of molecular biology describes the two-step process by which the information in genes is used to direct the synthesis of proteins. The central dogma states that the information flow is unidirectional: from DNA to RNA to protein, but not from protein back to DNA or RNA. DNA Replication is the process by which a copy of a DNA molecule is made, ensuring the accurate transmission of genetic information. Transcription is the process of copying one strand of DNA into a complementary RNA sequence by the enzyme RNA polymerase. Translation is the process by which the sequence of nucleotides in an mRNA molecule directs the incorporation of amino acids into a protein on a ribosome.
DNA Packaging and Epigenetics
The approximately 2 meters of DNA in each cell must be packaged and organized within the nucleus, which is only about 10 micrometers in diameter.
DNA is packaged into chromatin, with the help of histone proteins. Histones form nucleosomes, around which the DNA is wrapped, creating a "beads on a string" structure. The chromatin can further condense into higher-order structures, such as the 30-nanometer fiber and the chromosome form, reducing the overall length of the DNA by up to 10,000 times. Epigenetics refers to changes in gene expression that are maintained through cell divisions without altering the DNA sequence. Epigenetic mechanisms include DNA methylation, histone modifications, and the action of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). DNA methylation, particularly in the promoter regions, can "switch off" genes by preventing the transcription machinery from binding. Histone modifications, such as methylation and acetylation, can also affect gene expression by altering the packaging and accessibility of the DNA. Non-coding RNAs, like miRNAs and lncRNAs, can regulate gene expression post-transcriptionally or by recruiting other epigenetic modifiers.
Transcription Start Site and Promoter Region
The Transcription Start Site (TSS) is the location where the conversion of DNA sequence into RNA sequence begins. The promoter region is the DNA sequence where the transcription machinery, including transcription factors and RNA polymerases, binds and activates gene expression. Exons are the regions of the gene that contain the protein-coding sequences, while introns are the non-coding sequences between the exons that are removed during RNA processing.
DNA Methylation
DNA methylation is the covalent addition of a methyl group to the 5th carbon of a cytosine residue, typically in a CpG dinucleotide. DNA methylation writers, known as DNA methyltransferases, add the methyl groups. DNA methylation readers, containing methyl-binding domains (MBDs), recognize the methylated CpG and cause downstream effects. DNA methylation erasers, the TET family of enzymes, can oxidize the methylated cytosine, leading to the removal of the methylation mark. DNA methylation in the promoter region is generally associated with gene silencing, as it prevents the transcription machinery from binding and activating gene expression.
Histone Modifications
The histone proteins, which form the core of the nucleosomes, have flexible N-terminal tails that can undergo various post-translational modifications.
which produces either a regulatory or a messenger RNA. In this case, the transcript is a primary miRNA, which forms a typical hairpin loop structure. This primary miRNA undergoes several processing steps to become the final miRNA with regulatory function.
Processing of Primary MicroRNA into the Mature Form
First, the double-stranded stem of the primary miRNA is recognized by the protein DGCR8. An enzyme called DROSHA associates with DGCR8 to form the microprocessor complex, which is able to cut the RNA into a smaller precursor miRNA. This precursor miRNA is then exported into the cytoplasm by the transporter molecule EXPORTIN 5.
In the cytoplasm, the precursor miRNA is recognized by a large RNAse protein called DICER. DICER cleaves the stem loop and forms a short double-stranded miRNA molecule. In the next step, an Argonauts protein AGO 2 interacts with DICER to bind the miRNA. The miRNA is unwound, and one strand is released. The remaining strand, called the guide strand, interacts with AGO 2 and some additional proteins to form the RISC (the RNA induced silencing complex). This complex can now be guided to its target and inactivate one or multiple genes.
Mechanisms of Gene Silencing by MicroRNAs
The messenger RNA of a target gene is complementary to the sequence of the miRNA, enabling base pairing. Once bound, the RISC complex can either cut the messenger RNA, which will be further destroyed by the cell, or inhibit translation by preventing the ribosome subunit from binding. In both cases, the messenger RNA will not be translated into a protein, and the gene is silenced.
Potential of MicroRNAs in Medicine
Since their discovery in the 1990s, major parts of the miRNA pathway still remain unclear. However, with their essential role in many biological processes, miRNAs offer great potential for medicine and might lead to key treatments of various diseases in the future.
Long Non-Coding RNAs (lncRNAs)
Definition and Characteristics of lncRNAs
Long non-coding RNAs (lncRNAs) are defined as ncRNA molecules that are longer than 200 nucleotides and do not encode for proteins. They have been discovered very recently, and the function of only a few of them has been characterized.
lncRNAs are typically found at much lower levels than mRNAs, and their expression is often restricted to tissue-specific or time-specific developmental patterns. In contrast to protein-coding genes, the primary sequences of lncRNAs tend to show very little conservation. However,
lncRNAs from closely related species may share conservation of secondary and tertiary structures through regions of structural motifs, suggesting that the role of lncRNAs in gene function may be retained despite a lack of primary sequence conservation.
Regulatory Functions of lncRNAs
Though the functional roles of most lncRNAs remain to be elucidated, it is evident that lncRNAs exert regulatory functions in normal biological processes. lncRNAs have been shown to be involved in processes including transcriptional activation, transcriptional repression, chromatin remodelling, and RNA splicing regulation through a variety of mechanisms.
These mechanisms include: 1. lncRNAs serving as scaffolds to bring proteins together, such as binding chromatin remodelling complexes to change chromatin states and alter gene expression. 2. lncRNAs bringing proteins to specific regions of DNA or RNA through complementary base-pairing. 3. lncRNAs acting in cis, close to where they are transcribed, or in trans, away from their site of synthesis.
Implications of Aberrant lncRNA Expression
Aberrant lncRNA expression is thought to be the result of somatic mutations, which can lead to cancer. Additionally, a growing body of evidence supports a role for lncRNAs as circulating biomarkers and in infectious, metabolic, and neurodegenerative diseases.
Significance of lncRNA Research
Long non-coding RNA research is an exciting and rapidly expanding field. Through this research, we can enhance our understanding of biological processes and better elucidate the potential of lncRNAs as biomarkers and therapeutic targets for important human diseases.
Transcription Factors and DNA Binding
DNA Binding of Transcription Factors
Transcription factors bind DNA at the level of the major groove. This is because they are specific factors that bind to DNA, and the minor groove is too narrow for their binding. The sugar-phosphate backbone and histones are not the sites of transcription factor binding.
RNA Structure and Localization
RNA is usually single-stranded, and this is true regardless of the reason. The assertion that RNA is single-stranded is correct, but the reason provided in the text (that RNA is found in the nucleus and cytoplasm) is not the correct explanation for this assertion.
