Lecture 12 Flashcards
posttranscriptional factors
plays an equal, if not more significant, role compared to transcriptional control
mechanisms of posttranscriptional gene regulation
- control of alternative splicing
- mRNA stability
- translation
- RNA silencing
alternative splicing
- generates different forms of mRNA from identical pre-mRNA
- expression of one gene gives rise to numerous proteins with similar and different functions
- increases the number of proteins made from one gene called isoforms
casette exons
3 exons with 2 introns between them
alternative 5’ or 3’ splice sites
4 exons with 2 introns between them, leaving the second and third exon together
intron retention
3 exons with 2 introns between them
mutually exclusive exons
4 exons with 3 introns between them
alternative promoters
3 exons with 2 introns between them
alternative polyadenylation
3 exons with 2 introns between them
steady-state level of mRNA
- amount of mRNA in cell available for translation
- determined by combination of transcription and mRNA degradation rates
half-life
- mRNA s degraded at some point after synthesis
- lifetime of mRNA varies
- regulated by cell needs
what are the pathways of degradation?
- exoribonuclease enzymes: shorten length of poly-A called deadenylation dependent decay
- decapping enzymes: removes 7-methylguanine cap mRNA now unstable
- endonuclease cleaves mRNA internally
phosphorylation
the most common type of posttranslational modification
kinases
catalyze the addition of a phosphate group to ser, tyr, and thr amino acid side chains
phosphatases
-enzymes that remove phosphate
epigenetic trait
-a stable, mitotically and meitocally heritable phenotype that results from changes in gene expression without alterations in the DNA sequence
epigenetics
the study of the ways in which these changes alter cell and tissue specific patterns of gene expression
epigenome
-refers to the epigenetic state of a cell
what has epigenetic been implicated in?
- progressive restriction of gene expression during development
- allele-specific expression in gene imprinting
- environment genome interactions during interactions during prenatal development that affect adult phenotypes
- human genetic disorders
- the loss or alteration of other epigenetic states can result in cancer
epigenetic process
- stably alter gene expression patter and/or transmits the alteration at cell division
- includes cytosine methylation
- post-transcriptional modification of histone proteins and remodeling of chromatin
- RNA based mechanisms
methylation
- reversible, addition of methyl groups
- epigenetic changes
histone modification and chromatin remodeling
- alter the accessibility of genes for transcription
- epigenetic changes
methylation
-occurs on cytosine bases adjacent to guanine called CpG dinucleotides, which are clustered in regions called CpG islands
CpG islands
- located in and near promoter sequences adjacent to genes
- adjacent to essential genes are unmethylated and available for transcription
- other genes are methylated and transcriptionally silenced
heterochromatic methylation
-maintains chromosome stability by preventing translocations and other chromosomal abnormalities
histone modification
-important epigenetic mechanism of gene regulation
what is chromatin composed of?
-DNA wound around an octamer of histone proteins to form nucleosomes
where do histone modification occur?
-conserved amino acid sequences in the N-terminal histone tails, which protrude from the nucleosome
what do chemical modifications of histones do?
-alter the structure of chromatin, making genes accessible or inaccessible for transcription
how can amino acids in the N-terminal region of region of histones?
-modified by acetylation, methylation, and phosphorylation
acetylation by histone
- acetyltransferase opens up the chromatin structure
- makes genes available for transcription
removal of acetyl groups
- by histone deacetylase closes the configuration
- silences genes by making them unavailable
histone code
the sum of the complex patterns and interactions of histone modifications that change chromatin organization and gene expression
monoallelic expression (MAE)
only one allele is transcribed, while the other allele is transcriptionally silent
what are the three major classes of MAE
- parent of origin monoallelic expression: imprinting
- random monoallelic expression: inactivation of the X chromosome
- random monoallelic expression of autosomal genes
what do imprinted genes show?
- parent of origin
- the expression of only the maternal allele of the paternal allele
- occurs during gamete formation
what produces allele specific imprinting and subsequent gene splicing?
differential methylation of CpG rich regions
what happens when a gene is methylated and imprinted?
it remains transcriptionally silent during embryogenesis and development
what happens in the pattern of imprinting in mammals?
- it is reprogrammed every generation
- when gamete formation begins in female/male germ cells, both chromosomes sets have their imprints erased and are each reprogrammed by changing the pattern of methylation to carry a female/male imprint that is transmitted to the next generation through the egg/sperm
where does reprogramming occur?
in the parental germ line and in the developing embryo just before implantation
-after implantation, differential genomic remethylation recalibrates which maternal and paternal alleles will be activated
what do most implanted genes encode for?
growth factors or other growth-regulating genes
where is the origin of most imprinted disorders?
during fetal growth and development
BWS
- Beckwith-Weidemann Syndrome
- disorder of imprinting
- caused by abnormal patterns of DNA methylation resulting in altered patterns of gene expression
random inactivation of an X chromosomes
- about half of embryonic cells randomly inactivate the maternal X chromosome and the other half inactivate the paternal X chromosome
- silencing over 900 or so genes
- once silenced it remains silent
where are the 4 places that MAE genes can be throughout the genome
- expression of both alleles (biallelic expression)
- expression of only the maternal allele
- expression of only the paternal allele
- expression of neither allele
what can alter gene expression?
- environmental agents including nutrition, chemicals, and physical factors such as temperature
- affects the epigenetic state of the genome
