Genetics

• Epigenetic trait

  stable mitotically and meiotically heritable phenotype

  that results from changes in gene expression without alterations in the DNA sequence.
• Epigenetics 


  study of ways changes alters the cell and tissue specific patterns of gene expression.
• Epigenome


  epigenetic state of a cell
• We can alter the genome without changing the DNA sequence by


  DNA methylation/demethylation

  Acetylation/ deactylation of Histone- (histone code)

  Action of non-coding RNA molecules
• DNA Methylation: the Methylome


  tissue and cell specific

  can change not fixed
• • DNA methylation in mammals takes place

  After DNA replication

  during cell differentiation of adults cells
• Methylation is catalyzed by a family of enzymes called DNA methyl transferases (DNMTs)


  DNMT1 maintains methylation pattern through DNA duplication

  DNMT2 and 3 create methylation pattern
• Methylation occurs most often

  on the cytosine adjacent to a guanine, CpG doublets in DNA on both strands and it prevent binding of transcription factors
• CpG islands

  • Methylatable CpG-rich regions not random but concentrated

  70 % of CpG are on the promoter region
• Hypomethylated genes

  cell cycle

  transcription

  rna proccessing
• DNA Methylation


  e located in repetitive DNA sequences located in heterochromatic regions of the genome including the centromere
• DNA Methylation: Formation of Heterochromatin

  prevents translocations and other chromosomal abnormalities from occurring.

  chromosomes in mammalian females are inactivated by converting them into heterochromatin
• Histone acetyltransferase

  enzymes that adds an acetyl group to the lysine on the histone

  Histone no longer binds to DNA and transcription can occur

  histone deacetylase guided by methylome removes acetyl group
• Histone Deacetylase (HDAC) Activity


  recruited to the site of methylated dna

  removes acetyl so lysine becomes back positively charged

  tight packing
• Writers chromation modifier


  proteins that add chemical groups to DNA and histones

  Protein methyltransferase

  Histone acetyltransferase
• readers chromatin proteins


  proteins that interpret these chemical modifications on dna and histone

  Tudor domain- containing proteins

  MBT domain-containing proteins

  chromodomain- containing proteins
• Erasers chromatin modifiers

  proteins that remove the chemical groups on histones

  Histone deacetylase

  Lysine demethylase
• Short ncRNAs

  • miRNA (microRNA)

  • siRNA (short interfering RNA)

  • piRNA (piwi-interacting RNA
• miRNA and siRNA


  Processed by into short RNA molecules (~25 nucleotides),

  bind to the RISC complex (protein)

  This binding prevents the translation of targeted mRNA, stopping the production of proteins.
• piRNA

  Interacts with PIWI proteins,

  21-35 nucleotides in length.

  silence transposable elements.

  aid in forming heterochromatin and DNA methylation.

  role in combating viral infections.
• Long ncRNAs

  found close to a real gene

  can interfere with the real gene’s expression
• Long ncRNA (lncRNA) 4 models of action

  Decoy

  Adapter

  Guide

  Enchancer
• The decoy model


  lncRNA binding sites compete with transcription initiation sites on protein coding genes to prevent transcription.
• The adapter model

  lncRNA acts as a platform or adapter for two or more proteins to form active DNA-binding protein complexes
• The guide mode


  lncRNA recruits n guides protein complexes to specific loci.
• The enhancer model

  lncRNA binds to regions upstream or downstream of genes forming enhancerlike loops to regulate gene action
• Monoallelic Gene Expression types

  Parent of Origin Monoallelic Gene Expression – Imprinting

  Random X-inactivation

  Random pattern of allele inactivation of autosomal genes
• Monoallelic Maternal expression 1 allele active

  dad gene is methylated

  mom is not methylated
• Random X-inactivation

  X-inactivation center contains (non-coding RNA that coats the other chromosome and inactivate it)
• Random pattern of allele inactivation of autosomal genes

  autosomal gene coded for

  immunoglobins

  Odorant receptor

  interleukins
• What could possibly go wrong with epigenetics?

  Environmental agents AND Artificial reproductive technology

  can affect the epigenetic state of the genome
• Emotional Influence on Epigenetics

  High maternal nurturing leads to high levels of serotonin in brain, causing hypomethylation , acetylation and increased gene expression.

  this increases their adaption to stress and passed on phenotype to their kids .
• Dietary influence on Epigenetics

  Folic acid , vitamin B12 and choline are methylation precusors

  the lower methylation the more yellow the mouse coat colour
• A woman who smokes when she is pregnant.

  causes epigenetic changes in the three generations at once.
• Mutations in chromatin remodeling proteins 


  are linked to the development of cancer
• Rubinstein-Taybi Syndrome

  mutation in Histone acetyl transferase cause silencing of tumor supressor protien.
• BRCA1(tumor suppressor gene)


  Interacts with Histone deacetylase.

  it is normally hypomethylated (actively transcribed)

  when mutated it cause hypermethylation n inactivated n cause cancer
• Beckwith Wiedemann Syndrome


  an imprinting disorder on chromosome 11p15.5

  50% cases caused by loss of methylation on ic2 on maternal chromosome.

  20% from paternal unipariental disomy
• Genes expressed maternally

  H19 non coding RNA

  KCNQ1 (potassium channel)

  CDKN1C (cell cycle inhibitor)
• genes expressed paternally

  IGF2 (Growth factor)

  KCNQ10T1 (Long non-coding RNA)