genetics final

• epigenetics


  a change in gene expression caused by events that do not change the underlying DNA sequence. Mechanisms provide the link between environmental factors and phenotypical changes during a lifetime.
• Epigenetic mistakes


  reversible and provide drug targets , dynamic due to DNA and Histone modifications
• key processes in epigenetic regulation

  writing, erasing reading
• epigenetics regulate


  gene transcription, post transcriptional processing,mRNA translation and protein functions at molecular levels
• DNA methylation


  The addition of methyl groups to bases of DNA after DNA synthesis; may serve as a long-term control of gene expression. does not interfere with base pairing and is the best understood epigenetic modification
• CpG islands


  a group of CG sequences that may be clustered near a promoter region of a gene. The methylation of the cytosine bases usually inhibits transcription.
• EWAS (epigenome-wide association studies)


  detects changes in DNA methylation in CpG islands in epialleles associating with disorders or other epigenetic modifications (histone modifications)

  
• Key mechanism for genomic imprinting

  DNA methylation - all epigenetic modifications are erased in the early development of germline and prevents parthenogenesis

  
• histone modification


  changes in the structure of histones that make it more or less likely that a segment of DNA will be transcribed involved in genomic imprinting in mice

  
• H3.3


  histone variant that maintains a transcriptional activation
• CENP-A


  centromere function and kinetochore assembly
• H2AX


  DNA repair and recombination
• H2AZ


  gene expression and chromosome segregation
• macroH2A


  transcriptional repression, X-chromosome inactivation
• histone methylation


  the condensing of chromatin structure (heterochromatin), prevents transcription

  
• Chromatin Modification of Methylation (lysines)


  residues modified- K-me1 K-me2 K-me3

  functions regulated- transcription, repair
• Chromatin Modification of Methylation ( arginines)


  Residues modified- R-me1 R-me3a R-me2s

  functions regulated- transctiption
• Chromatin Modification of Acetylation


  Residues modified- K-ac

  functions repaired- transcription, repair replication, condensation
• histone acetyltransferase (HAT)


  histone modifying enzyme that loosen chromatin structure by adding acetyl groups to histone proteins
• Histone deacetylases (HDACs)


  remove acetyl groups from histones
• Histone Methyltransferase (HMT)


  methylates lysine and arginine in the histone tails
• histone demethylases (HDMTs)


  remove methyl groups from histones
• DMNT1 ( writer)


  MBD protein ( reader)

  TET- eraser
• Histone Acetylation


  The attachment of acetyl groups to certain amino acids of histone proteins to neutralize the positive charges associated with nucleosomes

  
• Crosstalk between histone modifcations

  positive influence of one modification over another is shown by an arrow and the negative effect by a dish line

  
• recruitment of binding proteins to modified sites

  downstream reactions and functions such as domains used for the recognition of methylated lysines, acetylated, phosphorylated serines. Proteins found associate preferentially with modified versions of H3 and H4

  
• histone reader proteins


  posses specialized domains that recognize and bind to specific histone modified sites and large transcription complexes can bind to multiple histone modifications

  
• gene repression


  5-methylcytosine, H3K9me2, H3K27me3 are promoter genes that inhibit TSS to silence gene expression

  
• Gene expression


  cytosine, H3K36me3, K3k4me3 are promoter genes that activate TSS and gene expression
• Functional consequences of gene expression

  NURF complex from gene expression contains BRTG recognizing H3K4me and a component remodeling chromatin

  
• Functional consequences of DNA repair foci

  Crb2 protein of fission yeast is recruited to DNA repair foci during a DNA repair response and is partly tethered by association with methylated H3 and phosphorylated H2A

  
• Functional consequences of DNA replication

  HBO1 acetyltransferase is an ING5-associated factor and tethered to sites of replication vias methylation H3K4 and HBO1 binds to MCM proteins at replication sites and evidence shows HBO1 augments formation of the preinitiation complex required for DNA replication

  
• Propagation of DNA methyl marks

  
• epigenetic propagation through mitosis

  parental nucleosomes with modified histones produces two daughter cells and only half have modified histones leafing to parental pattern of histone modification re-established by reader-writer complexes that recognize modifications they catalyze
• Modifying protein complex


  recognizes a DNA sequence or epigenetic signature and do not disassociate from replicating DNA until the passage of replication fork moves them and can immediately modify new chromatin following chromatin reassembly
• Proliferating cell nuclear antigen


  a key factor in DNA replication and cell cycle regulation
• propagation of histone code after DNA replication

  
• DNA methylation during embryogenesis

  
• Epigenetic Drugs for Cancer treatment

  DNMTi, HATi, HDACi, SIRTI, HDMi, HMTiX

  
• major writer proteins


  acetyltransferases and methyltransferases