Overview of Regulation, Epigenetics PDF

Overview of regulation, epigenetics DNA methyltransferases July 2011, David Goodsell http://doi.org/10.2210/rcsb_pdb/mom_2011_7 Thank you for many excellent and creative genetics reflections! Submissions included: A rap Collage Paintings...

Overview of regulation, epigenetics DNA methyltransferases July 2011, David Goodsell http://doi.org/10.2210/rcsb_pdb/mom_2011_7 Thank you for many excellent and creative genetics reflections! Submissions included: A rap Collage Paintings Digital art Podcast A comic strip Sculptures Reflective writing Poems Please give me feedback on how things are going! https://forms.gle/BTazPKnj28vF4qQh8 Review At the molecular level, a gene is a segment of DNA used to make a functional product (either an RNA or a polypeptide) The central dogma describes the flow of genetic information in the cell from DNA to protein DNA RNA Protein Review DNA RNA Protein Gene expression is the process by which the information within a gene is used to produce a functional product which can (along with environmental factors) determine a trait For the rest of the Molecular Genetics module we will focus on regulation of gene expression at various stages of the central dogma. Regulation of gene expression DNA Transcription mRNA Translation Protein Regulation of gene expression DNA Transcription mRNA Translation Protein Epigenetic regulation involves changes in gene expression that be passed from one generation of cells to the next and are reversible, without a change in the sequence of DNA. More on this today! Regulation of gene expression DNA Transcription mRNA Translation Protein Transcriptional regulation involves controlling whether or not transcription occurs as well as to what extent a gene is transcribed. Examples: repressors and activators Regulation of gene expression DNA Transcription mRNA Translation Protein Post-transcriptional regulation involves controlling gene expression at the RNA level. Examples: alternative splicing, riboswitches Regulation of gene expression DNA Transcription mRNA Translation Protein Translational regulation involves controlling the translation process, such as the rate at which translation occurs. This process is significantly Example: changes in numbers of tRNAs less well understood than transcriptional regulation Regulation of gene expression DNA Transcription mRNA Translation Protein Post-translational regulation involves controlling the activity to proteins. Examples: cofactors, covalent modifications Regulation of gene expression DNA Transcription mRNA Translation Protein Non-coding RNAs are RNAs that to do not encode a protein. They are involved in regulation at various stage. We will talk about this to wrap up this module! Talk to a neighbor: Why have cell evolved to regulate gene expression at so many different levels? How is the “response time” to adjust gene expression and the capability of the cell to respond to its environment different at each stage? DNA Transcription mRNA Translation Protein Regulation of gene expression DNA Transcription mRNA Translation Protein Epigenetic regulation involves changes in gene expression that be passed from one generation of cells to the next and are reversible, without a change in the sequence of DNA. Molecular mechanisms of epigenetic regulation Epigenetic changes play an important role in development (change throughout the life of an organism) and can be impacted by the environment Several types of molecular change underlie epigenetic regulation DNA methylation Chromatin remodeling Localization of histone variants Covalent histone modification  Review - DNA methylation DNA methylation is the covalent attachment of methyl groups (-CH3) It is carried out by DNA methyltransferase DNA methylation usually inhibits gene transcription Review - DNA methylation Unmethylated Hemimethylated Fully methylated DNA methylation is heritable DNA, not previously methylated, may become methylated by de novo methylation The hemimethylated DNA is recognized by DNA methyltransferase which makes it fully methylated through maintenance methylation Your turn Discuss with a neighbor: What is the function of the promoter and the enhancer? Which process of the central dogma might be impacted by methylation near these sites? Epigenetic regulation by DNA methylation Methylation near the promoter (typically in the enhancer region) generally reduces the level of transcription. Chromatin remodeling Chromatin remodeling involves changing the structure of the chromosome by moving, removing, or rearranging nucleosomes Chromatin remodeling Regions of the chromosome can be categorized into heterochromatin which is tightly compacted and typically transcriptionally inactive and euchromatin which is less condensed and is transcriptionally active Chromatin remodeling Facultative heterochromatin describes regions that can change between euchromatin and heterochromatin Euchromatin can be compacted to form heterochromatin HP1 (heterochromatin protein 1) bridges nucleosomes and makes them more compact Heterochromatin can bind to the nuclear lamina Patterns in the chromatin can be passed to daughter cells Heterochromatin patterns are established during embryonic development Constitutive – same in all cell types Facultative – cell specific Talk to a neighbor Why do you think the formation of heterochromatin reduces gene expression of those regions of the chromosome? Why might different cells types have different heterochromatin patterns? Chromatin remodeling by changing the positions of nucleosomes ATP-dependent chromatin remodeling involves using the energy from ATP to drive changes in location and/or composition of nucleosomes This can increase or decrease transcription Chromatin remodeling by removing nucleosomes ATP-dependent chromatin remodeling involves using the energy from ATP to drive changes in location and/or composition of nucleosomes This can increase or decrease transcription Chromatin remodeling and gene expression Moving or removing nucleosomes can result in nucleosome-free regions that allow transcription factors to bind and transcription to occur Localization of histone variants ATP-dependent chromatin remodeling involves using the energy from ATP to drive changes in location and/or composition of nucleosomes Localization of histone variants There are five main types of histones (H1, H2A, H2B, H3 and H4) A few histone genes have accumulated mutations that alters the amino acid sequence, these are histone variants Localization of histone variants Histone variants can alter the structure of the chromatin. Histone variants near the promoter can impact the transcription of a gene. Covalent histone modification Over 50 enzymes have been identified in mammals that modify the amino terminal tails of histones Acetylation (COCH3), methylation (CH3), and phosphorylation (phosphate groups) are common Covalent histone modification Histone modifications can affect the level of transcription by influencing interactions within nucleosomes Acetylation makes the DNA wrap less tightly around the histones, making it more accessible to transcription factors, increasing transcription Talk to a neighbor: Covalent histone modification and histone variants can impact the pattern of heterochromatin. At what stage in the central dogma does covalent histone modification occur? At what stage do histone variants arise? Summary of molecular mechanisms of epigenetic regulation Type of Modification Description DNA methylation Methyl groups attach to cytosine bases in DNA, when this happens near promoters, transcription is usually inhibited. Chromatin remodelling Nucleosomes may be moved or removed. When changes occur near promoters, the level of transcription may be altered. Larger-scale changes in chromatin structure can also occur (e.g. Barr body formation) Covalent histone modification Side chains in the amino-terminal tails of histones can be covalently modified and the level of transcription may be altered Localization of histone variants Histone variants in specific positions, such as near the promoter, can affect transcription. The environment can have a significant affect on phenotype via epigenetic mechanisms The Agouti gene in mice promotes the synthesis of yellow fur pigment. Pregnant mice fed on a diet that contained chemicals that tend to increase DNA methylation The environment can have a significant affect on phenotype via epigenetic mechanisms The Agouti gene in mice promotes the synthesis of yellow fur pigment. Pregnant mice fed on a diet that contained chemicals that tend to increase DNA methylation DNA methylation inhibits the Agouti gene  The graph shows the methylation in the CpG island which is a region near the enhancer. Talk to a neighbor: What effect do you expect the methylation to have on the expression of the Agouti gene? Does the methylation data match your expectations for each phenotype?