eukaryotic gene regulation chapter 18. slide 2 of 25 overview eukaryotes can regulate gene...

Eukaryotic Gene Regulation

Chapter 18

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Overview

Eukaryotes can regulate gene expression at multiple stages from gene to functional protein Regulation of chromatin structure DNA methylation Transcription initiation factors Alternative RNA processing Protein degradation

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-- blue = DNA-- orange = RNA-- purple = protein

--Each of these is a possible site for regulation, but not all are used in any instance or cell

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How do we get different cell types?

Red blood cells, muscle cells, neurons…

Every cell has the same genes

Different cells express only a fraction of their genes

20% of cell’s genes are expressed

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Histone Acetylation

-- DNA level of regulation

-- Histone proteins have protruding “tails”-- Acetyl groups can be added to these tails-- Acetylated histones lose their + charge, and are unable to bind to other nucleosomes

-- Acetylated histones = transcription more likely

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Histone Code Hypothesis

Histone tails can be Acetylated, methylated, or phosphorylated

Methylation = condensation of chromatin

Phosphorylation = separation of histones

So which determines the proteins produced: acetylation or the specific combination of these modifications?

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DNA Methylation

DNA itself can be methylated as well

Actually methyl groups are attached to the nitrogenous bases of nucleotides Specifically cytosine

Methylated bases are not able to be expressed Remember methylation from Inactivated X

chromosomes?

Interfere with normal methylation = weird results

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Important Difference…

Histone acetylation = INCREASED transcription

DNA methylation = DECREASED transcription

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Why are identical twins different?

They have the same genome, so WTF?

Base-pair mutations are one way to get genetic diversity

Different DNA sequences may be methylated, this results in certain sequences being turned off So same DNA but phenotypic variation

Identical twins, but one has schizophrenia while the other does not Called epigenetic inheritance (traits that are NOT

contained on nucleotide sequences)

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Transcriptional Modification

Most important area of regulation or control of gene expression Was this true in prokaryotes?

Involves Enhancer regions on the DNA

Activator proteins bind to mediator proteins

The complex is called transcription initiation complex Transcription of the downstream regions is enhanced

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-- Activator proteins bind to the enhancer region of DNA

-- Activator proteins also bind to Mediator proteins + Transcription factors

-- Forms transcription initiation complex

-- Almost guarantees that the gene will be expressed

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-- Activator proteins bind to enhancer DNA region

-- Different activator proteins = different gene transcribed & expressed

-- Activator proteins = directors of transcription in eukaryotes

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-- Spliceosomes can splice the primary RNA transcript differently

-- Creates different proteins

-- Fruit fly gene = 38,000 different combinations of proteins

-- Yet again, is phenotypic variation due to genetic sequences?

Alternative RNA Splicing

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siRNA Cure for Ebola?

1.5% of genome codes for proteins

Even smaller amount codes for RNAs (tRNA, mRNA, rRNA)

So is any part of the 98% ever transcribed?

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miRNA

microRNAs are capable of binding complementary sequences in mRNA molecules

Usually degrades the mRNA it binds OR blocks translation of the mRNA

1/3 of all genes regulated via miRNAs

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RNA Interference (RNAi)

Inject dsRNA molecules into a cell

This turns off gene expression of those genes with same sequence as the dsRNA

Small Interfering RNA (siRNA) were the dsRNA responsible for the interference

How did this lead to a treatment for Ebola? Ebola is an RNA based virus What about HIV? Hepatitis A or C? common cold? Dengue fever? influenza? H1N1, H5N1?

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Skip 18.4

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Cancer Genes

Oncogenes = cancer-causing genes

Proto-oncogenes = genes that codes for proteins that promote normal cell growth

Proto-oncogenes can become oncogenes Leads to an increase in protein production OR an increase in the activity of normal protein

production Either leads to TOO MUCH mitosis

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Tumor-Suppressor Genes

The produced proteins inhibit cell division

If a mutation decreases production of these products, cell division will accelerate

2 ways to get neoplastic growths (cancer): Mutation which alters proto-oncogenes into oncogenes

Over-produces protein OR hyperactive protein production This interferes with usual mechanism of cell cycle regulation

Mutation interferes with tumor-suppressor genes Insufficient production leads to mitotic hyperactivity

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Again…

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Cell CycleStimulatorPathway

Mutation in ras?

-- Activity even though no growth factor has been received by the RTK

-- Outcome = Excessive Mitosis

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p53 gene-- Commonly called the “guardian angel of the genome”

-- Halts cell cycle by binding CdK proteins

-- Allows time for DNA repair

--p53 is also directly involved in DNA repair

--p53 initiates apoptosis if DNA damage is beyond repair

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MultiStep Model of the Development of Colorectal Cancer

eukaryotic gene regulation chapter 18. slide 2 of 25 overview eukaryotes can regulate gene...

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different proteins

different activator

histone proteins

different gene

dnaactivator proteins

enhancer region of dna

enhancer dna region

dna methylationdna