TY  - CHAP
M1  - Book, Section
TI  - DNA Methylation and Epigenetic Silencing of Genes in Cancer
A1  - Herman, James G.
A1  - Baylin, Stephen B.
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
PY  - 2019
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - DNA  methylation  is  a  modification  made  postreplicatively  to  DNA;  it  takes  place  in  mammalian  genomes  at  cytosines  that  are  located  5′  to  a  guanosine  (CpG).  DNA  methylation  uses  S-adenosylmethionine  (SAM)  as  the  donor  for  a  methyl  group,  which  is  transferred  to  the  5  position  of  the  cytosine  ring  in  a  reaction  catalyzed  by  three  known  biologically  active  DNA  methyltransferase  enzymes  (DNMTs)  in  mammals.In  the  mammalian  genome,  CpG  dinucleotides  are  distributed  asymmetrically.  Most  areas  of  the  genome  have  been  depleted  of  these  sites  through  spontaneous  deamination  of  the  methylcytosine  base,  which  changes  it,  in  replicating  DNA,  to  a  thymidine.  More  discrete  regions,  often  associated  with  gene  promoters,  retain  the  predicted  numbers  of  CpGs;  these  stretches  of  approximately  0.4  to  4-5  kb  have  been  termed  CpG  islands.  The  promoter  regions  of  almost  half  of  mammalian  genes  contain  CpG  islands  that  are  defined  as  having  a  ratio  of  CpG/GC  of  ≥0.6  in  a  DNA  area  with  an  overall  GC  content  of  ≥55%.In  the  CpG-depleted  genomic  areas,  70-80%  of  candidate  CpG  sites  are  methylated.  The  function  of  this  methylation  may  relate  to  the  correlation  of  methylated  cytosines  with  areas  of  transcriptional  repression.  Most  of  the  mammalian  genome  is  packaged  into  late-replicating,  transcriptionally  silent  DNA,  and  CpG  methylation  may  help  lock  this  state  in  and  thereby  prevent  unwanted  transcription  of  foreign  sequences  such  as  viral  DNA  and  repetitive  elements.CpG  islands  associated  with  gene  promoters  are,  in  general,  not  methylated  in  normal  embryonic  and  adult  cells  whether  the  gene  is  being  actively  transcribed  or  not.  This  unmethylated  state  may  facilitate  maintenance  of  the  genes  in  a  transcription-ready  or  active  transcription  status.  In  transcriptionally  silent  genes  on  the  inactive  X  chromosome  of  females,  and  on  the  silenced  alleles  of  the  imprinted  genes,  the  promoter  CpG  islands  are  often  fully  methylated,  demonstrating  the  association  of  DNA  methylation  with  gene  silencing.The  relationship  of  gene  expression  and  cytosine  methylation  is  somewhat  different,  in  normal  cells,  for  CpG-poor  promoters.  In  these  regions,  methylation  of  individual  CpG  sites  again  correlates  with  transcriptional  repression.  However,  such  methylation  may  occur  in  normal  cells  when  the  gene  is  silenced  and  be  absent  in  the  same  cells,  or  same  cell  lineage,  when  the  gene  is  expressed.The  transcriptional  silencing  associated  with  promoter  region  CpG  methylation  is  mediated  by  a  series  of  chromatin  events  that  foster  heritable  transmission  of  the  repressed  expression  state.  These  include  maintenance  of  deacetylated  states  for  key  amino  acids  of  histones.  This  deacetylation  is  fostered  by  recruitment  of  histone  deacetylating  enzymes  (HDACs),  which  can  be  recruited  by  the  DNMTs,  by  a  family  of  methylcytosine-binding  proteins  (MBPs),  and  by  other  proteins  with  transcription  repression  properties.  The  transcriptional  repression  is  also  linked  to  methylation  of  key  histone  amino  acid  residues,  such  as  lysines  9  and  27  of  histone  H3  (H3K9  and  H3K27),  and  the  methylation  at  K9  may  actually  be  critical  for  targeting  DNA  methylation  to  transcriptionally  repressed  gene  promoters.In  cancers  of  all  types,  the  patterns  of  DNA  methylation  differ  dramatically  from  those  in  normal  cells  and  involve  both  losses  and  gains  of  modified  CpG  sites.  The  CpG-poor  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
Y2  - 2024/04/20
UR  - ommbid.mhmedical.com/content.aspx?aid=1181403665
ER  -