Flashcards in Genetics Deck (33):
What are the 3 primary mechanisms of epigenetic regulation?
DNA methylation, post translational modification of histones, regulation by non-coding RNAs
Where are epigenetic regulations most likely to be in use?
What happens if epigenetic regulations aren't working properly?
What is epigenetics?
Transcription or translation modified or influenced without altering genetic sequence, may be inherited in a stable fashion, may be influenced by the environment
What is imprinting?
Parent-of-origin determines whether some genes are expressed or not
The imprinted gene = inactivated gene
Inheritance process independent of classical Mendelian inheritance, and must be able to influence transcription
Epigenetic changes established in the germ line and maintained throughout mitotic divisions
Imprinting is important in neuro development
What is somatic mosaicism?
Somatic mosaicism occurs when the somatic cells of the body are of more than one genotype
What are normal functions of epigenetics?
-Transcriptional control of developmental genes and tissue-specific genes
-Inactivation of X chromosomes in females
-Inactivation of some growth genes according to parent of origin (imprinting)
-Mediation between the genome and the environment (aging, environmental chemicals, learning)
What happens in DNA methylation?
Does not affect matching nucleotides (C-G still works), DOES influence how other entities an bind to DNA
Hypermethylation of CpG island will cause gene to "shut down", can persist from parental germ line into the zygote
What happens in histone modification?
Histones wind and unwind DNA
Acetylation of lysine residues in the tail of H3 by histone acetyltransferase enzymes can cause: altered electric charge to separate DNA from histones or binding site for chromatin modifying enzymes and basal transcription machinery---> acetylation correlates with the ability to be transcribed
Deacetylation by histone deacetylase condenses chromatin structure, decreases gene transcription
Methylation may allow for binding of a transcriptional repressor protein
What is non-coding RNA?
Functional RNA molecule that is not translated into a protein
Transcribed from DNA, but located in an intron, between genes, or on antisense DNA strand
Translation: tRNA, rRNA, small nucleolar RNA, small nuclear RNA
Gene expression regulation: microRNA, small interfering RNA, piRNA, long noncoding RNA
What is microRNA? What is piRNA?
-Regulates about 60% of human coding genes
-Complementary to mRNA in 3'UTR
-Causes mRNA to decay, reduces gene produce
-miRNA controlled by CpG island methylation
-Transcriptional silencing in spermatogenesis
What is X inactivation? How does it work?
Selective epigenetic inactivation of alleles on one X chromosome
Due to X inactivation, all females are somatic mosaics for X gene activity
Descendants of each cell will have the same X inactivated from that time on
ncRNAs coat X chromosome DNA over very long distances to inactivate
How are females with one abnormal X chromosome affected in disease?
Duchenne muscular dystrophy: female will have normal to slightly elevated creatine kinase activity
Hemophilia A (Factor VIII): female will have normal to 50% Factor VIII
No total loss, just possibility of impaired function. Due to random X inactivation, females affected less than males who only have one X and no X inactivation
How does X inactivation affect women who carry an abnormal gene on one X chromosome?
Extent of phenotype determined by distribution of mosaicism
What are some characteristics of imprintable genes?
-One allele expressed in at least one body tissue
-Occur in clusters
-Alleles inherited through generations will change methylation and activity pattern depending on sex of transmitting parent
-Frequently involves CpG methylation
How are epigenetics disrupted in cancer?
-CpG methylation of tumor suppressor genes
-miRNA expression can act as oncogenes or tumor suppressors, so any changes to miRNAs can lead to lack of tumor suppressing abilities or increase in oncogenes
-piRNA in testicular tumors, snoRNA, lncRNA
How does a lack of miR200 cause cancer?
(1) CpG island hypermethylation of miR200 family
(2) Lack of miR200 transcription
(3) Permits expression of several transcriptional repressors
(4) Allows repression of E-cadherin gene normally responsible for cell-cell adhesion
(5) Permits epithelial-to-mesenchymal transition of cancer and allows cancer to invade
How can miRNAs be targeted for cancer therapy?
-If miRNA overexpression is causing cancer, inhibit miRNA function
-If miRNA suppression is causing cancer, restore miRNA function
Define malformation and state the recurrence risk.
Malformation- structural defect of an organ resulting from the abnormal formation of tissues (flawed process of formation from the beginning), can be isolated (eg. cleft lip) or part of a syndrome (eg. cleft lip as part of Trisomy 13)
Recurrence risk: risk of inheritance of syndrome OR 3-5% if isolated
Multiple anomalies w/ a single basic cause which occur independently rather than sequentially
Define deformation and state the recurrence risk.
Structural defect resulting from tissue damage and breakdown of otherwise normal structures
Ex. premature rupture of amniotic membrane --> tendrils wrap around baby during development --> cause constriction bands around hands and feet
Recurrence risk: <<1%
Abnormality in form or position of a body part caused by mechanical force (constraint) or secondary effects from a functional abnormality in fetus (i.e. something gets squished)
Structural defect or mechanical factor that leads to sequence of secondary effects (if --> then)
Ex. Potter sequence: renal agenesis (malformation) --> lack of amniotic fluid (baby urine) --> mechanical pressure on face, ears, hips, feet (deformation) --> lack of fluid for fetus to breathe in --> pulmonary hypoplasia (cause of death = baby can't breathe when they're born b/c alveoli aren't developed)
Define uniparental disomy.
Inheritance of both homologues of a chromosome or region of a chromosome from the same parent (no copies from other parent), occurs when trisomy of fertilized ovum is rescued by loss of 3rd chromosome
What happens in an embryo if uniparental disomy involves a segment of a chromosome? An entire chromosome? The entire genome?
Segment of a chromosome: 2 chromosomes are present, but there are regions of homozygosity and regions of heterozygosity-- can result in Prader Willi syndrome (maternal UPD) or Angelman syndrome (paternal UPD)
Entire chromosome: 2 copies of the exact same chromosome
Entire genome: ovarian teratoma (all maternal contribution) or hydatidiform mole of placenta (all paternal contribution)
What role does epigenetics play in cellular differentiation?
Oocyte and sperm have CpG methylation --> after fertilization, sperm immediately demethylates, but oocyte is slower
Before nuclei fuse, one round of DNA replication occurs --> remethylation begins to appear (opportunity to "reset" methylation)
What role does imprinting play in cloning of organisms and stem cells?
A lot of bad things happen when cloning organisms and stem cells, and imprinting would just make it worse
Shape of embryo is produced through axis development (craniocaudal, anteroposterior) and asymmetry development (determined by families of transcription factors)
What are HOX genes?
Family of developmental transcription factors (helix-turn-helix family) that binds right into DNA groove to influence transcription
Form in 4 clusters on 4 chromosomes
Form a temporospatial arrangement- they are on the same chromosome and are closely related, but act at different times to cause development of different organs/parts of the body
Define morphogens and describe their mode of action.
Morphogens- small molecules that diffuse and create concentration gradient --> gradient has different effects on cell fates
Mode of action: bind to receptors of intracellular inducible transcription factors
Provide examples of small molecules that are morphogens.
Retinoic acid (binds near HOX genes), steroid hormones, thyroxine
NOTE: Isotretinoin (13-cis-retinoic acid) has a low affinity for retinoic acid receptors but may be converted intracellularly to metabolites that are agonists --> contraindicated in pregnancy b/c of teratogenicity (causes birth defects in children like hydrocephaly, microcephaly, intellectual disabilities, ear and eye abnormalities, cleft palate and other facial deformities, heart defects)
Process by which 1 part of an embryo causes adjacent tissues to change through diffusion of substances