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ANAT 381 > Genomic Imprinting > Flashcards

Genomic Imprinting Flashcards

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1
Q

How are Imprinted genes expressed - generally

A

Monoallelically in a parent of origin specific manner

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2
Q

Describe imprinted genes

A

Typically = 2 copies of each gene, one copy of each gene on each homologs, amount of mRNA and expression depends on both copies
IMPrinting = only one or other expressed= parent of origin dictates what allele expressed, only pat or mat

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3
Q

What is imprinting an ex of

A

Classic epigenetic effect = stably maintained - for a while (not always life long or in every cell), broadly distributed

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4
Q

Describe early evidence for imprinting in mammals - exps

A

Mouse embryos constructed by pro nuclear transfer exps = need male and female pronuclei to develop
If have 2 fem nuclei = no extra embryonic tissues, partial dev, not viable
If have 2 male nuclei = poor embryonic dev = no viable
Exps = 1980s
Other species can do this = parthenogenesis- NOT mammals

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5
Q

Describe early evidence for imprinting in mammals - do you need both male and female contributions to the embryo

A

YUHHHHHHHHHH

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6
Q

What does imprinting account for

A

Non equivalence of maternal and paternal genomes
Newer exp = reveals that imprinting is why cannot use 2 same pronuclei alone
Oocyte nucleus in which 2 maternally silenced genes have been activated = turn these 2 genes on =rescues dev = overcomes lack of imprinting and creates fatherless mice

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7
Q

Where are imprinted genes typically found

A

In large clusters = tend to form domains or clusters

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8
Q

What are imprinted gene clusters controlled by

A

Imprinting control regions = ICRs
Region important for whole pattern, specific master control region
Ig-dmr = differentially meyhtlated region - part of ICR

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9
Q

What happens when delete icr

A

Deletion of icr on paternal allele disrupts the expression pattern for entire cluster of genes

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10
Q

Name and describe functions of imprinted genes - 4

A

(Share functional characteristics)
1- tend to have high levels of expression in prenatal stages
2- growth and metabolism, neurological development, developed of placenta
3- clinical relevance = genetic disorders involving defective imprinting
4- imprinting is often disrupted in cancer cells - epigenetic disregulation

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11
Q

Describe evolutionary origins of imprinting - emergence

A

Emergence of imprinting linked to that of the placenta-marsupials (yolk like placenta) and placental mammals have imprinting
MONOTREMEs do not (mammals that do not have placenta)

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12
Q

Describe evolutionary origins of imprinting - parental conflict hypothesis - gen

A

Imprinted genes reflect competition between males for limited female resources

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13
Q

Describe evolutionary origins of imprinting - parental conflict hypothesis - Mat and pat

A

If a single female mates with multiple males, males want to ensure their offspring outcompete those from competitor males whereas the female wants to allocate ressources to all offspring evenly - regardless of dad
Males look out for own genetic interest

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14
Q

Describe evolutionary origins of imprinting - parental conflict hypothesis - conclusions

A

Posits that maternally expressed genes are growth restricting for fetus, opposite for paternally expressed genes - growth promoting (not all genes but most fit the idea)

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15
Q

What is the key epigenetic mark for imprinting

A

DNA meth
Imprinting starts with dna meth

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16
Q

What are imprinting genes usually associated with

A

CpG islands that are differentially methylated on maternal and paternal alleles - between (= differetially methylated regions or dmrs) = CORRESPOND TO ICRs defined genetically

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17
Q

How is imprinted established - icrs

A

By dnmt3a - enzyme, in germ line
Maintained by dmnt1

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18
Q

When is imprinting erased

A

During germ cell migration to developing gonads, erased at specific stage - during germ cell dev

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19
Q

What else is involved with gene imprinting - mods

A

Not just dna meth
Histone mods, non coding RNA’s also involved - recent examples of imprinted genes not associated with DMR but instead marked with H3k27 methylation

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20
Q

Describe the 2 instances of global reprogramming of dna meth in dev

A

Period of global epigenetic remodeling = all and meth removed
Happens when germ cells (pcgs) migrate to genial ridge = E9.5-11.5= all dna meth erased
Imprinting established after this

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21
Q

When does imprinting establishment occur

A

During germ cell dev after genome wide erasure of dna methylation
DNA CpG methylation erased genome wide in pcgs = diff timings tho for male and female

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22
Q

Describe timing of imprinting

A

Male = immediately after = E13.5
Female = bit longer, not until embryo post natal = P21
Set own pattern of imprinting - best to do here since erased all other, so can establish patterns

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23
Q

Name/describe the 2 types of imprinting mechanisms involving dna methylation

A

Maternally methylated
Paternally methylated
How establish methylation = male vs female

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24
Q

describe the MAT types of imprinting mechanisms involving dna methylation

A

Maternally methylated DMRs and ICRs located at promoters and block promoter function - occurs at CpG islands

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25
describe the PAT types of imprinting mechanisms involving dna methylation
Paternally methylated dmrs and icrs are located between genes and affect enhancer function - more distant Less studied
26
Describe Igf2-h19 imprinted domain - gen
Domain with 2 genes = igf2 and h19 next to each other in genome Mat = enhancer downstream h19 genes, no igf2 but yes h19 Pat = igf2 but no h19 - differential methylation between the 2 genes = h19 not transcribed Supports the theory - growth vs non growth - mat/pat
27
What is igf2
Insulin like growth factor expressed fro paternal allele
28
What is h19
Non coding rna expressed from mat allele
29
What happens when igf2 ko
Have reduced size at birth but only if get ko allele from father - bc imprinted gene - inherited from mom = no phenotypes since not expressed
30
What is an enhancer
DNA element that binds sequence specific tfs and activates transcription of genes in same vicinity on chromosome
31
What does igf2-h19 icr have
Enhancer blocking activity Ex= normally enhancer can turn on neomycin resistance gene, but if put icr between E and neo = does not work anymore Insertion of icr region between a heterologous enhancer and promoter prevents enhancer activity
32
What is an insulator
Insulates gene or promoter from enhancer = basis of how icr establishes pattern of imprinting
33
What regulates binding of insulator protein ctcf
Methylation of icr
34
Describe when icr methylated vs not methylated and relationship with ctcf
When icr unmethylated - mat - blocks enhancer from activating igf2 (through ctcff binding) Methylation of ice in pat prevents ctcf from binding and allows enhancer to work
35
What is function of ctcf
Important chromosome organizing factor that regulates the formation of loops in chromosomes Can influence long range, interactions between diff elements on chromosome Ctcf function very sensitive to methylation as well
36
Describe methylation of icr and regulation of ctcf on mat
Ctcf binds = what gives you blocking between enhancer and promoter Enhancer blcoking depends on dna binding protein= ctcf Turns on h19 but not igf2 since icr region there
37
Describe methylation of icr and regulation of ctcf on PAT
Icr methylated so ctcf cannot bind anymore = enhancer turns on igf2 = no enhancer blocking function anymore
38
What does maternal specific methylation typically do
Typically silences promoters of long non coding rnas located INSIDE protein coding genes
39
Describe igf2r gene in MAT
Icr in middle of igf2r gene = in coding region of gene Igf2r = gene encoding igf2 receptor, gets expressed from mat alleles specifically Methylation occurs here on mat allele = non coding rna not transcribed since methylated = tgf2r expressed
40
Describe igf2r gene in PAT
Unmethylated in pat = mtheylation regulates a diff promoter for a non coding rna that gets transcribed within igf2r gene = Non coding rna transcribed in opp direction and starts in middle of igf2r gene = igf2r cannot be expressed at Same time
41
Describe kcnq1 gene in MAT And PAT
Mat = me at icr in middle of gene = fine transcription Pat = Icr = not methylated = antisense rna Do not know how its affecting other linked genes nearby
42
What is incRNA
Transcribed antisense to igfr2 and kcnq1
43
How does IncRNA transcription lead to silencing within imprinted domain
Conserved way = hidden promoters- act of turning on promoter interferes with gene transcription= act of antisense transcription interferes with sense transcription (especially if it crosses the sense promoter) Rna itself recruits chromatin modification enzymes that silence transcription (like kcnq1ot1 rna recruits prc2 )- in some cases = non coding rna produced has consequences for cell function
44
Describe kcnq1ot1 rna recruits prc2 - effect of this
Complex = target non coding rna can dictate region = seems to be related to how the effects might be able to spread to other regions of chromosome = rna can interact with and activates other epigenetic remodeling complexes that can spread and act on adjacent genes = some evidence, One target for this = prc2 complex = non coding rna in this region can dictate fcuntion of prc2 in this region
45
What context is imprinting established in
Context of different genome wide dna meth patterns in developing germ line How established differential meth = has to do with dna meth patterns in developing oocyte vs sperm Histone mods help set up these patterns
46
Describe oocyte dna me pattern
Low in promoters Specific enrichment in bodies of genes transcribed in developing oocyte - maternal icrs = in middle of gene bodies Oocyte primed by overalls genome methylation pattern
47
Describe sperm dna me pattern
Less specific Low in promoters Present in most/all gene bodies Present in intergenic regions Pat icr always in intervening regions, = lots of methylation = some priming established by something that happens in sperm broadly
48
Where is dna methylation specifically maintained in zygote - describe situation
At icrs in zygote Have to be maintained for a long time through many cell divisions during embryonic dev Have to be able to survive global epigenetic remodeling period DNA methylation erased genome wide but imprinted methylation maintained When = During pcgs migration- allows imprinting to be established then at zygote to 2/8 cell stage = removes dna meth, not complete since imprinted regions maintained
49
How is dna methylation specifically maintained at icrs in zygote
Factors that bind to icrs- dna binding protein H3k9 methylation - important role
50
Describe zfp57 in imprinting maintenance- gen
DNA binding protein Binds specifically to when it’s methylated = protects methylation All found in same place - by chip seq = icrs, sfp57, setdb1, h3k9me3 All found in same place = all set up by zfp57 being able to bind these
51
Describe zfp57 in imprinting maintenance- specifics = fam? Where binds? Recruits?
Member of zinc finger family of dna binding proteins Specifically binds to methylated TGCCGC at icrs (protects methylation at that site, specific sequence found, rich in c and g) Recruits h3k9 methyltransferase setbdb1 = to protect
52
You discover a new species of mouse with large ears that talks in a high pitched voice. Propose a way that you could identify the imprinted genes in this species. Assume you will need to use a genome-wide profiling method in adult tissue. What do you think will be the biggest challenge you will encounter?- exp ideas
Create mat and pat and see if passes down Hardest part = figuring out which is pat or Mat allele Can do rna seq - but still wont know, finding specific CpG islands in middle of gene - do not know if mat or pat but could guess its an icr and look closer
53
Describe identification of imprinted genes using genomics - gen
Best bets are either RNA-seq (RNA levels) or whole genome bisulfite sequencing (DNA methylation) BUT... * Need to be able to experimentally distinguish maternal and paternal alleles at many genes * Difficult to achieve in human studies
54
Describe identification of imprinted genes using genomics - exp
Mouse studies involving crosses of two different inbred strains have been the most valuable-in these strains individuals are homozygous for virtually all genetic markers, but the markers are different across strains Offspring heterozygous for many genetic markers, so can distinguish paternal and maternal alleles by sequence! Gen = way male or fem contribute - dif, make them diff enough so have markers that can distinguish - use inbred lines = so can distinguish - off spring heterozygous for all the makers = can distinguish since sequence diff
55
How do you go from genomics to imprinted genes
RNA-seq (RNA levels) or whole genome bisulfite sequencing (DNA methylation) will give you genes that show monoallelic expression (from only the maternal or paternal allele) or monoallelic DNA methylation
56
How do you know that these patterns arise from imprinting (= something that is really due to parent of origin?)
Mechanism depends on parent of origin so do same exp and switch mom and dad between strains - pattern of imprinting willl be switched = track parent of origin If imprintin= monoallelically expressed genes should now be expressed from other allele
57
Name 4 developmental disorders linked to imprinting
Prader willi and angelman syndromes Beck with wiedemann and silver russel syndromes
58
Describe clinical phenotype of angelman syndrome
Happy disposition, laughter, widely spaced teeth, wide mouth, stiff upheld arms, broad stance
59
Describe clinical phenotype of prader willi syndrome
Central obesity, short stature, small hands and feet, mild facial dysmorphism
60
Describe what PWS and AS are typically caused by - gen
Deletion of entire imprinted domain on chromosome 15 - leads to dev problems, defect in region of chrom Involves deletions that affects all or most of entire region of chrom 15 Whole bunch of genes expressed in an imprinted way - parent of origin specific way Genetic = effects at an imprinted region can have very divergent phenotypes dependent on transmission from mom or dad
61
What specifically causes Angelman syndrome
Maternal transmission of deletion (UBE3A)
62
What specifically casues prader wili syndrome
Paternal transmission (due to SNORD116)
63
Describe clinical phenotype of beckwith wiedemann syndrome
Macroglossia - big tongue, ear creases Neonatal gigantism - wight of babies is in 98th percentile 1000 fold increased chance of developing tumours
64
What are BW and SR caused by
Effects of multiple diff imprinted genes misexpressed and no genetic cause Epigenetic errors Loss of imprinting at kcnq1 and igf2 loci, other imprinted loci can be affected as well Caused by epigenetic errors that property establish imprinting - basis not known
65
Why does BW and SR happen?
Some underlying genetic Basis maybe - undiagnosed genetic cause Maybe environmental factors (Sporadic)
66
Describe imprinting and ART
Could art impinge on these mechanism of imprinting Some studies= expression of imprinted genes affected by art Some evidence that BWS increases incidence of Art Potential environmental effects

ANAT 381 (24 decks)

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