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Epigenetic Regulation of Gene ExpressionCase Study: Dosage Compensa2on
WHAT IS EPIGENETICS
= Heritable changes in gene func2on that don’t involve changes in the gene/DNA sequence
• Study of mito2cally and meio2cally heritable changes in gene func2on that cannot
be explained by changes in the DNA sequence
• 2 major mechanisms
o Methyla2on
o Modifica2on of histone proteins
• Mechanisms modulate transcrip2onal poten2al of genes (regula2on of gene
expression)
METHYLATION IN EUAKRYOTES
• Forma2on of 5 methylcytosine via DNA methyl transferase
• Occurs in CpG islands
o Found upstream in regulatory regions in eukaryo2c genes
o Associated with repression of transcrip2on
GENOMIC IMPRINTING
• Major tenet of Mendelian Gene2cs à origin of allele does not affect its func2on
o Both parents contribute equally to inheritance
o Reciprocal crosses yield iden2cal results
§ Heterozygotes do not display recessive traits
• NOT true for X linked genes in mammals à dosage compensa2on
• Small number of autosomal genes = excep2ons to this rule
o DNA methyla2on of either paternal or maternal allele (genomic imprin2ng)
Eg. Prader Willi & Angelman Syndrome
• Result of deel2ons in the q11-13 region of chromosome 15
• If maternal chromosome dele2on à Angelman syndrome
• If paternal chromosome dele2on à Prader Willi syndrome
• Leads to loss of 2 genes from chromosome 15
o UBE3A = ubiqui2na2on of proteins
o SNRPN = involved in proteins encoding proteins involved in pre-mRNA splicing
• Ordinarily, maternal SNRPN is methylated and paternal UBE3A is methylated
o Humans are hemizygous for these two genes and hence why dele2ons are
causa2ve agents of the two syndromes
o Done in order to prevent genomic conflict
§ Allows for resource alloca2on depending on demands of the individual
o Methyla2on of these genes only resets in germline produc2on
, HOW DOES METHYLATION BLOCK TRANSCRIPTION
• Transcrip2on factors read DNA via major groove and recognize asymmetric paderns
of hydrogen bond donors and acceptors
• Addi2on of methyl groups prevents binding of transcrip2on factors or recruits
chroma2n remodeling proteins to change the structure of chroma2n to prevent
binding
• NB does not interfere with H bonds between bases
1) Addi2on of hydrophobic methyl group alters the ability of certain TFs
2) Recruits MBD proteins to recruit chroma2n remodeling proteins to form repressive
chroma2n
*methyla2on ofen leads to repression of gene expression but it can lead to increased gene
expression!
CHROMATIN STRUCTURE
• DNA = complexed by histone proteins (H2A, H2B, H3 and H4) into nucleosomes
linked by H1 (linker protein)
• Nucleosomes condense to form chroma2n
Condensed chroma2n = repressive (heterochroma2n)
Open chroma2n = permissive (euchroma2n)
à chroma2n packing = dynamic
• Centromeres and telomeres = cons2tu2ve heterochroma2n (always 2ghtly packed)
• Faculta2ve heterochroma2n
o Barr bodies in mammals
o Around one or two genes at a 2me one can pack the chroma2n closely
• Repressive chroma2n prevents accessibility of GTFs and thus RNA pol binding + TIC
forma2on
POST TRANSLATIONAL MODIFICATIONS OF HISTONE TAILS
• Tails of histones protrude from nucleosome
• Most common = acetyla2on and methyla2on
o Performed by acetyl transferase and methyl transferase enzymes
§ Markers are recognized by chroma2n remodeling proteins
• Different markers are recognized by different proteins
• Can have ubiqui2na2on and phosphoryla2on
• Lysine and arginine = most common residues modified (posi2vely charged residues)
• Different regions of the chromosome have different modifica2ons
o Leads to open or closed chroma2n
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