BIOL 2960 Lecture 32: Eukaryotic Transcriptional Elongation and Repression

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Washington University in St. Louis
Biology And Biomedical Sciences
Biology And Biomedical Sciences BIOL 2960
Kunkel Barbara

Lecture 32 Sunday, April 23, 2017 2:59 PM EUKARYOTIC TRANSCRIPTIONAL ELONGATION AND REPRESSION Remember: • Readers: bind modified histone amino acids • Writers: modify histone amino acids • Erasers: restore modified histone amino acids to unmodified form Transcriptional Elongation • Acetylation: loosens the chromatin to make it more accessible • Methylation: ○ Substitution of H on lysine with methyl group (CH3) ○ Can be methylated 1, 2, or 3 times ○ Distinct protein binding determinants, so number of methyl groups depends on the protein being used -- more specific than acetylation ○ Positive charge remains, so the purpose is to serve as a recruitment site, no functional change • Chromatin is super dense, so RNA Pol can't just go, it has to barge through the big tangle ○ The C-terminal domain (CTD tail of RNA Pol II) must be phosphorylated by TFIIH kinase to initiate transcription. ○ The phosphorylated tail then provides a binding site for factors involved both in processing the transcript, and in regulating the "activity" of transcribed chromatin (chromatin modifiers). ○ As such, it is an integrator or coordinator of the gene expression machinery. Several of these are required to "open" chromatin to allow the passage of RNA Pol, then to close it after the polymerase has passed through. ○ Much more complicated than what happens in a bacterial cell because the chromatin is inactive in front of and behind the Pol, it only opens when it passes through via acetylation, and then is closed again via de-acetylation. Repression by Histone Deacetylases • Histone deactylases associate with transcriptional co-repressors ○ Just like some transcriptional activators recruit co-activators with histone acetylase activity, some repressors recruit co-repressors that has histone deacetylase activity. ○ Several different transcriptional factors, from both yeast and metazoans, have been shown to bind to these corepressors to bind to these corepressors ○ Examples: ▪ In yeast, GAL1 transcription is repressed in the presence of glucose by the glucose- induced binding of a repressor called Mig1, which recruits co-repressor with HDAC activity ▪ In human cells, E2F is a transcription factor (regulator protein) that controls genes involved in cell-cycle progression and binds to the RB (retinoblastoma) protein (tumor suppressor protein). E2F can function as an activator or a repressor, depending on whether it associates with RB to form a co-repressor complex with HDAC activity, or in the absence of RB a co-activator with HAT activity □ During the cell cycle, cells pause in the G1 phase at the restriction point □ Passage through the restriction point requires growth factor signaling, which activates a protein kinase □ E2F binds at promoters of cell-cycle regulated genes  If RB binds to it with a HDAC, transcription is repressed -- active repression  Later in G1, HAT shows up and transcription is activated ◊ Growth factor activates kinases that phosphorylate RB at the restriction point ◊ Phosphorylated RB does not bind to E2F, so HAT can come Epigenetics • Define: the method of inactivating genes via the repression of chromatin structures (not mutations) -- cannot be opened so can prevent certain genes from being expressed • Two modifications associated with repressed chromatin and epigenetic silencing: ○ Methylation at C5 of cytosines in CpG dinucleotides (C and G side by side) ▪ 5-methylcytosine in CpG sequence: ▪ ▪ DNA methylation is established by a "de novo" DNA methyl transferase (DNMT), which puts a methyl group at the 5 position of cytosines found in CpG sequences ▪ DNA methylation is maintained by a maintenance DNMT that puts a methyl group at the 5 positions of C's located in CpG sequences that are complementary to the methylated CpG sequences ▪ Then, 5MethylC Binding Domain proteins recognize 5meC modified DNA and recruit HDACs to maintain chromatin in an "off" state (t
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