Epigenetics 3 Flashcards
What factors influence the level of gene expression and which genes are expressed?
Histone modifiers
Chromatin remodelers
RNA polymerase
Transcription Factors
What is genetic imprinting?
People inherit two copies of their genes—one from their mother and one from their father. Usually both copies of each gene are active, or “turned on,” in cells. In some cases, however, only one of the two copies is normally turned on. Which copy is active depends on the parent of origin: some genes are normally active only when they are inherited from a person’s father; others are active only when inherited from a person’s mother. This phenomenon is known as genomic imprinting.
tl;dr Some genes are only methylated in eggs and unmethylated in sperm and vice versa
Which allele is said to be imprinted?
The non-expressed allele
How many genes in the human genome are imprinted?
> 70 genes identified
What happens to imprinted genes in human diseases?
Deregulation of imprinted genes
What kind of inheritance pattern is gene imprinting?
Non-mendelian patterns that exhibit parental-origin effects
What is suggested about genomic imprinting from disease symptoms?
Role of imprinted genes in growth regulation during embryonic and post-natal development, brain function and behaviour
What common conditions are associated with genomic imprinting?
Beckwith-Wiedemann syndrome
Prader-Willi syndrome
Angelman syndrome
Wilms tumour
What is beckwith-Wiedemenn syndrome?
Embryonic and placental overgrowth and predisposition to childhood tumours
What causes Beckwith-Wiedemann syndrome?
Genetic and epigenetic changes in a region of about 1 megabase on chromosome 11p encompassing 15 genes the majority of them being imprinted.
Patients have both chromosome 11 copies from the father (too many active genes from father not enough from mother)
Which key gene overexpression from paternal chromosome causes Beckwith-Wiedemann syndrome?
IGF2
CDKN1C
Increased expression of IGF2 and suppression of CDKN1C are believed to be the major cause of the disease
Which chromosomes express IGF2 and CDKN1C maternal or paternal?
IGF2 normally on paternal
CDKN1C on maternal chromosome
How is imprinted locus in 11p15 normally controlled in maternal chromosome?
In maternal chromosome: Enhancer region produces CTCF which binds to ICR1 region which becomes an insulator region so RNA polymerase binds to promotor and expresses H19 but is insulated from binding to IGF2 by the insulator region. Methylation of ICR2 prevents activation of suppressor gene for KCNQ1 gene meaning this gene is expressed as well as CDKN1C
How is imprinted locus in 11p15 normally controlled in paternal chromosome?
H19 suppressed and IGF2 expressed due to methylation of ICR1
ICR2 is not methylated and so suppressor gene is active and so CDKN1C and KCNQ1 are suppressed
What chromosomes are the defects seen in Angelman and Prader-Willi syndrome?
15q11 - q13
What are the symptoms of Angelman syndrome?
Severe mental retardation
Microcephaly
Lack of speech
Frequent laughter
What causes Angelman syndrome?
Deletion of maternal 15q11 - q113 (Loss of maternal UBE3A gene)
What are the symptoms of Prader-Willi syndrome?
Mild mental retardation, obesity, short stature
Deletion of paternal 15q11 - q13 (deficient snoRNAs expression of paternal allele)
What kind of genes are expressed in the 15q11 - q13 region under normal circumstances?
MKRN3m MAGEL2, and NDN are produced only in paternal chromosomes.
PWRN1, C15ORF2, and SNURF-SNRPN are expressed more in paternal chromosomes than maternal chromosomes
UBE3A and ATP10A are expressed more in maternal chromosomes than paternal chromosomes
What happens to paternal chromosome gene expression in prader-willi syndrome?
Decreased paternal snoRNA produced (PWRN1, C15ORF2, and SNURF-SNRPN)
What is X inactivation caused by?
Early in development of most female mammals one X chromosome is completely inactivated in every cell. Overall transcription dosage of chromosome X genes is equal in males and females (dosage compensation)
When does X inactivation usually occur?
64 - 128 cell stage in mouse zygotes
What is dosage compensation the result of?
Chromosome X genes are expressed equally in males and females
Which X chromosome is inactivated usually?
It is completely random. (each cell has an independent choice)
