6. Role of NRs in cancer

• Chromatin status


  Chromatin structure plays a key regulatory role in gene expression
• Chromatin states


  • Heterochromatin (condensed, transcriptionally silenced)
  • Euchromatin (transcriptionally active)
• Heterochromatin


  • Condensed DNA, hypo-acetylated histones, hyper-methylated histones
• Euchromatin


  • Transcriptionally active, hyper-acetylated histones, hypo-methylated and hyper-phosphorylated
• Histone H3 modifications associated with transcriptional activation

  • H3-serine 10 phosphorylation
  • H3-lysine 9 acetylation
  • H3-lysine 4 methylation
  • H3-lysine14-acetylation
  • H3-lysine4/36/79-methylation
• Histone H3 modifications associated with transcriptional repression

  • H3 and H4 lysine deacetylation
  • H3-lysine 9 methylation
  • H3-lysine 27 methylation
• Histone lysine methyltransferases (KMTs)


  Enzymes that methylate histone lysine residues
• Histone lysine methyltransferases


  • MLL
  • EZH2
  • G9a
  • SET
• Nucleosome remodeling complexes


  ATP-dependent complexes that reposition nucleosomes along DNA to promote transcription factor binding
• p160 coactivators


  Steroid receptor coactivators that enhance nuclear receptor-mediated transcriptional activation
• p160 coactivators


  • SRC-1
  • SRC-2/TIF2/GRIP
  • SRC-3/ACTR/AIB1
• p300 and CBP


  Major lysine acetyltransferase coactivators that enhance transcriptional activation
• pCAF


  p300/CBP-associated factor, a lysine acetyltransferase coactivator
• Other lysine acetyltransferase coactivators

  • MOZ
  • MORF
  • MYST
  • TIP60
• p160 coactivators are highly similar but exhibit distinct expression patterns and non-redundant functions
• LxxLL motif


  Leucine-x-x-leucine-leucine motif required for coactivator binding to nuclear receptors
• Coactivator modifications


  Can regulate their interactions with nuclear receptors and transcriptional activity
• Mediator complex


  A large multi-subunit coactivator complex that recruits RNA polymerase II to promoters
• NCoR and SMRT


  Nuclear receptor corepressor complexes that repress transcription in the absence of ligand
• CoRNR box


  Motif in corepressors that mediates binding to nuclear receptor ligand binding domains
• Chromatin status


  Influences gene expression
• Corepressors


  NCoR & SMRT
• Thyroid receptors (TR) were known to possess intrinsic transcriptional repressive functions in the absence of T3
• NCoR


  Nuclear receptor corepressor
• SMRT


  Silencing mediator of retinoic acid and thyroid hormones
• Ligand binding


  Decreases the affinity of the receptor for Corepressors
• NCoR & SMRT are closely related and highly similar
• NCoR & SMRT are recruited to Type II nuclear receptors (RARs, TRs, RXRs etc) in the absence of an agonist
• NCoR & SMRT are also recruited to Type I receptors (AR, PR, ER) by Antagonists
• NCoR & SMRT


  Generalized transcriptional repressors
• NCoR & SMRT interact with additional transcription factors unrelated to nuclear receptors
• NCoR & SMRT interact directly via CoRNR boxes (L-x-x-x-I-x-x-x-I/L) with the LBDs of nuclear receptors
• NCoR & SMRT recruit Histone Deacetylases (HDACs) to the upstream regulatory regions of genes
• NCoR & SMRT interact with HDACs either directly or via homologs of the Sin3A proteins (first identified in yeast)
• HDACs


  Render the DNA-histone complex inaccessible to the general transcription machinery and thereby repress transcription
• Classes of HDACs


  • Class I: HDAC 1, 2, 3, 8 (homologous to yeast Rpd3p)
  • Class II: HDAC 4, 5, 6, 7, 9, 10 (related to yeast Hda1p)
  • Class III: related to yeast NAD+ dependent Sir2 family
  • Class IV: unique Zn-catalytic mechanisms: HDAC11
• The relative roles of each HDAC in NR-mediated repression is not well delineated
• HDACs play essential roles in temporal regulation of expression and epigenetic repression
• Histone lysine and arginine methylation plays key roles in transcriptional regulation
• It had been assumed that histone-lysine methylation was effectively irreversible considering the high thermodynamic stability of the C-N bond