Transcriptional and Post-Transcriptional Regulation of Gene Expression

{"type":"doc","content":[{"type":"heading","attrs":{"textAlign":null,"level":2},"content":[{"type":"text","text":"Transcriptional Regulation in Eukaryotes"}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Overview of Gene Regulation"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Gene expression in eukaryotes is tightly regulated at multiple levels, including chromatin structure, transcription, RNA processing, translation, and post-translational modification. Transcriptional regulation is a key control point, determining when and how much a gene is expressed."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"DNA accessibility"},{"type":"text","text":": Chromatin remodeling alters the accessibility of DNA to transcription machinery by unwrapping DNA from nucleosomes."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Transcription machinery"},{"type":"text","text":": RNA polymerase and associated factors are required for transcription initiation."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Regulatory proteins and ncRNAs"},{"type":"text","text":": These molecules bind DNA and each other to modulate RNA polymerase recruitment and activity."}]}]}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Gene Regulatory Architecture"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"The regulatory architecture of a gene includes core promoters, enhancers, silencers, insulators, and various transcription factors. These elements can be located near or far from the gene they regulate, and their interactions are essential for precise gene expression."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Core promoter region"},{"type":"text","text":": Immediately upstream of the gene, necessary for transcription initiation."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Distal regulatory elements"},{"type":"text","text":": Enhancers, insulators, and repressors can be located far from the gene, either upstream or downstream."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Transcription start site (TSS)"},{"type":"text","text":": The location where transcription begins."}]}]}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_1.png","alt":"Cis-regulatory elements and their interaction with transcription factors","title":null,"width":null,"height":null}},{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_2.png","alt":"Trans-regulatory elements and their effect on gene expression","title":null,"width":null,"height":null}}]},{"type":"heading","attrs":{"textAlign":null,"level":2},"content":[{"type":"text","text":"Cis- and Trans-Regulatory Elements"}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Cis-Regulatory Elements (CREs)"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Cis-regulatory elements are non-coding DNA sequences that regulate the expression of neighboring genes. They include promoters, enhancers, silencers, and insulators."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Promoters"},{"type":"text","text":": DNA regions (100–1,000 bp) immediately upstream of the TSS, containing binding sites for RNA polymerase and general transcription factors."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Enhancers"},{"type":"text","text":": DNA sequences that stimulate transcription from a distance, often by looping the DNA to bring the enhancer close to the promoter."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Silencers"},{"type":"text","text":": DNA elements that repress transcription when bound by repressor proteins."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Insulators"},{"type":"text","text":": DNA sequences that block the interaction between enhancers and promoters when positioned between them."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"promoter- "}]}]}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"image","attrs":{"src":"data:image/png;base64,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","alt":"","title":null,"width":null,"height":null}},{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_4.png","alt":"Enhancer-promoter looping and transcriptional activation","title":null,"width":null,"height":null}},{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_5.png","alt":"Stimulation of transcription by activator binding to an enhancer","title":null,"width":null,"height":null}}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Trans-Regulatory Elements (TREs)"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Trans-regulatory elements are typically proteins or non-coding RNAs encoded by genes that can regulate distant target genes. They include transcription factors, RNA polymerase, and various regulatory RNAs."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Transcription factors (TFs)"},{"type":"text","text":": "},{"type":"text","marks":[{"type":"bold"},{"type":"underline"}],"text":"Proteins "},{"type":"text","text":"that bind specific DNA sequences in promoters or enhancers to activate or repress transcription."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"RNA polymerase II"},{"type":"text","text":": The enzyme responsible for synthesizing pre-mRNA in eukaryotes."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Non-coding RNAs"},{"type":"text","text":": Such as lncRNAs and microRNAs, which can modulate gene expression post-transcriptionally."}]}]}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_9.png","alt":"RNA polymerase structure and function","title":null,"width":null,"height":null}},{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_10.png","alt":"Pre-initiation complex assembly at the promoter","title":null,"width":null,"height":null}}]},{"type":"heading","attrs":{"textAlign":null,"level":2},"content":[{"type":"text","text":"Mechanisms of Transcriptional Regulation"}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Promoters and Consensus Sequences"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Promoters contain consensus sequences such as the TATA box and CAAT box, which are recognized by transcription factors and are essential for the initiation of transcription."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"TATA box"},{"type":"text","text":": Facilitates the recognition and start of transcription."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"CAAT box"},{"type":"text","text":": Located further upstream, involved in promoter efficiency."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Each promoter responds to a unique combination of activator proteins, allowing for gene-specific regulation."}]}]}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Enhancers and Silencers"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Enhancers and silencers are regulatory DNA elements that can act at a distance from the promoter. Enhancers increase transcription when bound by activators, while silencers decrease transcription when bound by repressors."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Enhancers can function in either orientation and at variable distances from the gene."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Silencers are less studied but are crucial for gene repression."}]}]}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_7.png","alt":"Activator and repressor transcription factors binding to enhancers and silencers","title":null,"width":null,"height":null}}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Insulators"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Insulators are DNA sequences that block the action of enhancers on promoters when positioned between them. The CTCF protein binds insulators to create boundaries and protect genes from inappropriate regulation."}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_8.png","alt":"Insulator blocking enhancer-promoter interaction","title":null,"width":null,"height":null}}]},{"type":"heading","attrs":{"textAlign":null,"level":3},"content":[{"type":"text","text":"Transcription Factors: Activators and Repressors"}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","text":"Transcription factors can act as activators or repressors, influencing the assembly and stability of the transcriptional machinery at the promoter."}]},{"type":"bulletList","content":[{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Activators"},{"type":"text","text":": Stimulate and stabilize the basal transcription apparatus, often by altering chromatin structure."}]}]},{"type":"listItem","content":[{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"text","marks":[{"type":"bold"}],"text":"Repressors"},{"type":"text","text":": Bind to promoters or silencers to prevent activator binding or interfere with the basal transcription apparatus."}]}]}]},{"type":"paragraph","attrs":{"textAlign":null},"content":[{"type":"image","attrs":{"src":"https://static.studychannel.pearsonprd.tech/study_guide_files/genetics/sub_images/a39ef905_image_11.png","alt":"Transcription factors and mediator proteins at the 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