Epigenetics of Human Marie Černá Lecture No 426-H.
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Transcript of Epigenetics of Human Marie Černá Lecture No 426-H.
Interaction of environment and genotype
gene pool1 gene pool
2
gene pool3
gene pool4
gene pool5
external factor 1
external factor 2
external factor 3
external factor 4
external factor 5
epigenetic modifications
Epigenetic modifications
- allow interaction of environment with identical genotypes and by the way formation of their various phenotypes
- modifications of gene expression which do not involve nucleotide changes
- can be heritable
Metastable epialleles
- identical alleles
that are variably expressed
due to epigenetic modifications
that are established during life
- can be hereditary
Epigenetic modifications change level of gene
expression
Influence of environment:
- In utero
- Ex utero
Epigenetic modifications change level of gene
expression
They depend on
- environment (internal + external)
- age
- sex
Epigenetic modifications - genome is an open system
with biological clock• period of early pregnancy
• period of medium pregnancy
• period of late pregnancy
• early postnatal period (until 3 years)
• period of puberty (in ♀ 2 years early)
• period of mode exchange (30-40 years)
Reik W, Dean W, Walter J, 2001, Science, 293, 1089-1093.Epigenetic reprogramming in mammalian development
Epigenetic modificationsin monozygotic twins
Fraga et al., 2005, PNAS, 102, 10604-10609
in 65% pairs identical
in 35% pairs different
correlation with age and
with time spending together
Epigenetic modifications
• Chromosomal position effects
• Polycomb and Trithorax complexes
• Prions and prion-like phenomena
Inactivation of gene expressionheterochromatin – closed chromatin
DNA methylation of CpG islands
Histone modifications
- deacetylation (H3K9)
- methylation (H3K9, H3K27, H4K20)
- sumoylation
- ubiquitination
Activation of gene expressioneuchromatin – open chromatin
DNA hypomethylation of CpG islands
Histone modifications
- acetylation (H3K9)
- methylation (H3K4, H3K36, H3K79)
- phosphorylation
- ubiquitination
Mechanism of DNA methylation
Participation of protein complexes:
• DNA methyltransferases (DNMT)- DNMT 1 – maintenance methylation
- DNMT 3A+3B – de novo methylation
• Methyl-CpG-binding protein (MeCP)
Mechanism of histone modification
Participation of protein complexes:
• histone acetyltransferases (HAT)
• histone deacetylases (HDAC)
• histone methyltransferases (HMT)
• histone demethylases (LSD)
RNA interference
a natural process of gene expression silencing, at the stage of translation or transcription, by non-coding RNA:
1)short RNAs – obtained from digestion of double-stranded RNAs (dsRNAs)
2)long RNAs (> 200 nucleotides)
Targets of RNA interference
short RNAs:
• inactivation of RNA from viruses
• inactivation of RNA from mobile elements (transposons)
long RNAs:
• inactivation of X chromosome
Mechanism of RNA interference
Participation of protein complexes:• Dicer with RNase activity
• RISC (RNA-induced silencing complex)
• RITS (RNA-induced transcriptional silencing)
• PIWI proteins
short RNAs
1)micro RNA (miRNA)
2)short interfering RNA (siRNA)
3)Piwi-interacting RNA (piRNA)
short RNAs (in cytoplasm)
x small RNAs (in nucleus et nucleolus)
micro RNA (miRNA)
• 21-23 nucleotides
• Endogenic
• Binding to RISC• Partial recognition of complementary
sequence in 3’-UTR (nontranslated region)
• Inhibition of translation process by binding to target mRNA
short interfering RNA (siRNA)
• 20-25 nucleotides
• Exogenic
• Binding to RISC or RITS (chromatin modifications)
• Full recognition of complementary sequence in coding region
• Initiation of mRNA digestion/degradation
Piwi-interacting RNA (piRNA)
• 27-30 nucleotides
• Exogenic
• Binding to PIWI proteins
• Influence of epigenetic regulation
• Control of transposons silencing
Significance for diagnosis
Searching specific miRNAsin blood and urine of patientswith a goal to obtain biomarkers fordiagnostics and progress evaluationof disease (tumors)
In man there was described ≈ 2 500 miRNA.
Chromosomal position effects
Insulators – sequences along the DNA that attract particular proteins (CTCF protein) for the purpose of preventing distal enhancers from activating or silencing genes
insulator functions:
- establish the boundaries of regulatory domains
- modify chromatin structure
- affect nuclear organization
Polycomb and Trithorax complexes
maintain and propagate expression states (active or silent) of homeotic genes, HOX genes, throughout development by the counteracting activities:
- silencing through trimethylation of H3K27 by Polycomb complexes
- activation through trimethylation of H3K4 by Trithorax complexes
Prions and prion-like phenomena
An auto-regulatory loop – capable of maintaining persistent cellular characteristics
the structural inheritance – the faithful reproduction of a structure made of proteins
the regulatory inheritance – transgenerational continuing of established function of proteins, greatly influenced by the environment