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MolBio (Fach) / Lecture 5 (Lektion)

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• Epigenetic trait -stable,heritable phenotype resulting from changes in a chromosome without change of DNA-Sequence -stable in cell division -reversible -important in germ cell development and early embryogenesis
• Epigenomics Epigenetic changes in the level of whole genome 
• Epigenetics: Eukaryotes (in General) -precise and stable way to control gene expression and genomic stability -genomic stability:  -- silencing centromere,telomeres, transposable elements ensures:  ---correct attachment of microtubules ---reduces excessive recombination between repetitive elements ---prevents transposition
• Epigenator Enviromental signal which triggers epigenetic changes, leads to activation of initiator  Example: Temperature, metabolites
• Epigenetic initiator translates the epigenators signal identifies location on chromosome and binds DNA-sequence specific
• Epigenetic Initiator: DNA-binding-Proteins -binds via noncovalent interactions (alpha helix in protein domain)  -binds with atoms in major and minor groove and the sugar-phosphate backbone
• Epigenetic Initiator: ncRNA -functional RNA-molecule (transcribed:yes, translated:no) -short ncRNA + long ncRNA -regulate gene expression at transcriptional and post-transcriptional level
• ncRNAs involved in epigenetic process: ncRNA (<30nt) -miRNA (microRNA) -si(short interfering RNA) -piRNA (piwi-interacting RNA)
• ncRNA involved in epigenetic processes: Long ncRNA (>200nt) -forms complex with chromatin modifying proteins -results in modification of chromatin state (-> this influences gene expression)
• ncRNA involved in epigenetic processes: miRNA binds mRNA to induce: -cleavage -degradation  -block translation (feedback mechanism)
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• ncRNA involved in epigenetic processes: siRNA -post-transcriptional gene silencing: mRNA degradation -induces heterochromatin formation by binding to RNA-induced transcriptional silencing complex (RISC) 
• ncRNA involved in epigenetic processes: piRNA -chromatin regulation -supression of transposon activity (germ line + somatic cells )
• ncRNA: function -chromatin remodelling  -transcriptional regulation -post-transcriptional regulation -precursor for siRNA
• Epigenetic maintainer DNA-Methylation > methyl-group to 5´carbon of cytosin in CpG-Island  3 Enzymes (class: DNA-Methyltransferase) this represses genes expression different cell type = different methylation pattern  Non-CpG- cytosine methylation high in stem cells (may be critical for differentiation) global methylation (+non CpG-methylation) inverse proportional to level of differentiation
• PTM coordinated + correlated with DNA-methylation covalent, post-translational modification (PTM) PTM affects: gene expression, DNA repair amd chromosome condensation PTM includes: Methylation, Acetylation, Phosphorylation, Ubiquitylation, Sumoylation majority of PTM occur on N-terminal tail of histones PTM change condensation state and with that accessibility to DNA
• Histone Modification: Acetylation target: Lysine (K) residues adding of CH3CO - Groups 2 involved enzymes: -histone acetyltransferase (HAT) -histone deacetylase (HDAC) CH3CO-Group neutralizes positive charge of lysine -> decreased affinity between histone tail and negatively charged DNA
• Histone modification: Methylation target: lysine (K) and arginine (R) [both basic,+] associated with transcribed and silenced genes Arginine can be mono- and dimethylated Lysine can be mono-, di- and trimethylated Degree of this has a role in gene expression 2 Enzymes: -histone methyltransferase (HMT) -histone demethylase (HDM)
• Histone modification: Phosphorylation target: serine (S), threonine (T) and tyrosine (Y) [All have polar side chains] associated with transcriptional activation negative charge of phosphate -> repulsive force between histone and DNA  reversible 2 enzymes: -protein kinase (PK) -protein phophatase (PP)
• Histone modification: Ubiquitination target: H2A + H2B adding of ubiquitin (76 amino acid long protein) H2A ubiquitination -> repressive  H2B ubiquitination -> active and repressed genes  ubiquitination + methylation often cross talk
• Histone modification: sumoylation adding of SUMO-proteins (small, ubiquitin-like modifiers; ~100 amino acids long)  added by: specific ligases reversed by: proteases mark of transcriptional repression
• Histone variants encoded by different genes few amino acid difference in histone tail or globular central domain specific expression, localization and distribution patterns affect chromatin remodelling + histone modifications 
• Nucleosome remodelling Nucleosome = histone octamere + DNA change in structure of chromatin requires ATP (Enzyme=ATPase) may lead to: -dissassembly of nucleosomes -exchange of histone for variants -assembly of nucleosomes -movement of histone octamers
• Allelic imbalance = different ration of gene expression levels from each of two allels in diploid genome 5-20% of autosomal genes usually in early embryogenesis Reason: Variants in the DNA-Sequence 
• Monoallelic expression = only one of two copies is active 4 types: -somatic rearrangement -random allelic silencing or activation -genomic imprinting -X-Chromosome inactivation
• Somatic rearrangement = changes in DNA organization to activate only on gene at one gene copy  0,5 - 15% of autosomal genes random choice of one gene copy  EXAMPLE:  somatic rearrangement in immunoglobulin genes (B- & T-cells) Mechanism: cutting and pasting of DNA-sequences to rearrange genes in somatic cells to generate antibody diversity
• Random allelic silencing or activation expression from only one gene copy due to epigenetic changes random choice of one gene copy  specific cell type
• genomic imprinting epigenetic silencing of one gene copy in imprinted regions >100 genes known epigenetically marking goes according to the parental origin (parent-of-origin-mechanism) 
• X-Chromosome inactivation = epigenetic silencing of x-chromosome linked genes on one female chromosome random choice early embryogenesis
• X-Inactivation only expression of escape gene(s)  2 * dose of escape gene product induces Xist gene (X-inactive specific transcript) 3-7 day of embryonal development X-Chromosome in inactivated by methylation of cytosine, H4 histone hypoacetlyation and other histone modifications
• Insuline-like growth factor II (IGF2) key factor for growth and development maternally imprinted methylation of five CpG dinucleotides in IGF2 region >higher obesity rate: less methylation >smal body mass in adulthood: no epigenetic changes
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• Cancer epigenomics in cancer tissue DNA-methylation is reduced  Hypomethylation oncogene promotors  > lead to genome instability
• Aberration of the epigenome due to the ageing process changes in global DNA-hypomethylation DNA-methylation changes may predispose to cancer by inducing a more stem cell like state
• Pathological epigenetic Regulation: Rett-Syndrome Changes in MeCP2 gene (methyl-CpG-binding protein 2) which leads to reduced function normally this protein acts as transcriptional repressor changes in epigenetic ragulations
• Psychiatric disorders: Addiction to cocaine Histone acetylation UP Histone methylation DOWN DNA methylation UP Mechanism: -cocain exposure induces H3+H4 acetylation -cocain exposure reduces H3K9 dimethylation -cocain exposure (chronic) increases MeCP2 and MBD1 expression 
• Psychiatric disorders: Depression Histone acetylation DOWN Histone methylation UP DNA methylation UP Mechanism: -HDAC2 + HDAC5 (Histone deacetylase) are downregulated -methl marks on H3 are upregulated -increased DNA methylation levels at GABA

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