Epigenetics and diseases. Genetical analysis Irma takács

Transcription

1 Epigenetics and diseases Genetical analysis Irma takács

2 Epigenetic diseases Introduction Mechanism Diseases

3 Miracle: Identical DNA different cells EPIGENETICS

4 Epigenetics C.H. Waddington in the 1940s : Fusing the word genetics and epigenesis epi means above Modifications of the genetic information that do not alter DNA sequence Cell s ability to remember past events, such as changes in the external environment and developmental cues METASTABLE

5 Epigenetics Characteristics: Self-perpetuating heritable reversible Three criteria: Mechanism of propagation Evidence of transmission Effect on gene expression

6 Epigenetics Trans epigenetic signals: Molecules found in the cytoplasm Cis epigenetic signals: Are physically associated and inherited along with the chromosome on which they act

7 Epigenetics R Bonasio et al. Science 2010;330: Published by AAAS

8 Epigenetics Trans epigenetic signals: Transcriptional factors small ncrns molecules

9 Trans epigenetic signals TFs ncrnss: small and long R Bonasio et al. Science 2010;330: Published by AAAS

10 Cis epigenetic signals DNA methylation Changes in histones: Primary sequence (histone variant) Posttranslational modification Position relative to DNA sequence Others: non-histone proteins, higher order chromatin structure, nuclear localisation

11 DNA methylation CpG islands methyl group at the 5 position of the cytosine pirimidin ring Enzymes: DNA methyltransferase DNMT1: maintaining methyltransferase DNMT3A and 3B: de novo methyltransferase Methylated DNA is transcriptionally inactive

12 DNA methylation methylated DNA is INACTIVE transcriptionally WHY? answer: methylation of DNA itself may physically impede the binding of transcriptional proteins to the gene methylated DNA may be bound by proteins known as methyl-cpg-binding domain proteins, which recruit additional proteins to the locus, such as histone deacetylases and other chromatin remodeling proteins that can modify histones

13 Histone modification Altering chromatin structure Inhibit the binding of a factor to the chromatin template Creates a binding site for a particular protein Structure of histone: H2A and H2B H3 and H4 Most common site: H3 and H4

14 Histone modification 2 groups: small chemical groups: acetylation, phosphorylation, methylation ubiquitylation, sumoylation

15 Histone acetylation HAT and HDAC Sites: H3K9, 14, 18, 23, 56; H4K5, 8, 12, 16 acetylation: activating transcription deacetylation: repressing transcription change in charge bromodomain

16 Histone phosphorylation Kinases (pl. MAPK) Sites: H3 at serine Mainly in metaphase chromosomes durin mitosis and meiosis

17 Histone metylation histone lisine methyltransferase (HKMT) and histone demethylase sites: H3K4, 9, 27, 36, 79 and H4K20, arginin represses or activates depening on the position chromodomain

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20 Establishment of epigenetic state Environmental stimuli, developmental cues, internal events Converge on chromatin to shape the transcriptional landscape, and then it is converted into cis epigenetic signatures

21 Establishment of epigenetic state Transcriptional factors (Drosophila: Polycomb and trithorax group)? TFs directly recruit chromatin-modifying enzymes to their genomic targets TFs help transcription of DNMT genes and histone modifying enzyme genes

22 Establishment of epigenetic state small and long ncrnss long Published by AAAS R Bonasio et al. Science 2010;330:

23 Reinforcement and Spreading Histone posttranscriptional modifications and DNA methylation can be reinforced locally or spread to adjacent areas to form larger chromatin domains Epigenetic states can also be reinforced by cross talk among histone modifications and DNA methylation

24 Reinforcement and Spreading Trans: cell division (TF and ncrna) Cis: DNA methylation: DNMT1 Histone modification: 2 theory: Parental nucleosomes divides between descendent cells Small ncrnas which are generated during replication recruit chromatin-modifying complexes to reestablish heterochromatic signatures at the target loci

25 Published by AAAS R Bonasio et al. Science 2010;330:

26 Reversal Change in the ratio of TFs and histone modifying enzymes DNS demethylation: Active demethylation through oxidation TET-1-3 Base excision repair Histone modification

27 Summary of epigenetic states Metastable: Stable in order to keep their identity It has the ability to change when it is particularly needed

28 Diseases DNA methylation means transcriptional silencing Imprinting: methylated genes

29 Mechanism of diseases Maternal and paternal uniparental disomy

30 Classification of diseases Disorders of genomic imprinting: Prader-Willi and Angelman syndrome Beckwith-Wiedemann syndrome Silver-Russel syndrome Pseudohypoparatyreosis Disorders affecting the chromatin structure in trans: Rubinstein-Taybi syndrome Rett syndrome α-thalassaemia X-linked mental retardation ICF syndrome Methylen tetrahidrofolate reductase deficiency Disorders affecting the chromatin structure in cis: αδβ-thalassaemia and δβ-thalassaemia Fragilis X syndrome Facioscapulohumeralis distrophy

31 Disorders of genomic imprinting Prader-Willi and Angelman syndrome Beckwith-Wiedemann syndrome Silver-Russel syndrome Pseudohypoparathyreoitism

32 Prader-Willi syndrome deletion or UPD or imprinting: Deletion in 15q11-q13 of paternal chromosome Methylation in the same region of the maternal chromosome 1/10000 Dysfunction of hypothalamus

33 Prader-Willi syndrome symptomes: GLUTTONY general characteristics: infantile hypotonia, developmental delay, failure to thrive due to poor feeding, lethargy from 2 years of age: hyperphagia, severe obesity, short stature, secondary hypogonadism with genital hypoplasia, mild cognitive impairment physical characteristics: small hands and feet, almond-shaped eyes, thin upper lip neuronal symptomes: obsessive-compulsive behavior, anxiety, unhappy disposition, mild to moderate mental retardation

34 Prader-Willi syndrome Paternally inherited deletion Maternal chromosome is imprinted Exactly which gene is affected in imprinting is not known Candidate genes: ncrnas, SNURF-SNRPN (small nuclear ribonucleoprotein gén) and Necdin gene

35 Angelman syndrome deletion or UPD or imprinting: deletion in 15q11-q13 of maternal chromosome methylation in the same region of the paternal chromosome 1/20000

36 Angelman syndrome neuronal symptomes: happy disposition, smile frequently, unexplained bouts of laughter, severe developmental delay, very minimal verbal skills, balance problems, abnormal flapping movements, seizures microcephalia, prominent mandible and wide mouth happy puppet syndrome angel

37 Angelman syndrome Maternally inherited deletion UBE3A gene is affected UBE3A gene is transcribed only from the maternal allele, which is deleted Paternal is silenced

38 Beckwith-Wiedemann syndrome 11p15 paternal UPD, chromosome translocation, abnormal methylation 85% sporadic, 15% familial

39 Beckwith-Wiedemann syndrome somatic overgrowth predisposition to childhood embryonal malignancies main characteristics: macroglossia macrosomia increased size of internal organs omphalocele neonatal hypoglycemia embryonic tumors Wilms tumor, hepatoblastoma

40 Beckwith-Wiedemann syndrome 11p15 12 imprinted gene 2 imprinting region: ICR1: H19 and IGF2 ICR2: CDKN1C, KCNQ1, SLC22A1L IGF2 is overexpressed

41 Silver-Russel syndrome Genetically heterogenous 10% of cases result from maternal UPD for chromosome 7 or demethylation of ICR1 on chromosome 11p15, which causes biallelic expression of H19 and decreased expression of IGF2

42 Silver-Russel syndrome intrauterine growth retardation, difficulty feeding, failure to thrive, or postnatal growth retardation somatic growth abnormality, short stature often with asymmetry in adulthood intelligence normal with possible learning disability facial dysmorphism, asymmetric limbs

43 Pseudohypoparathyreoidism Functional hypoparathyreoidism despite normal parathyreoid hormone level 20q13.2 GNAS1 gene guanine nucleotide-binding protein Three upstream alternative first exons (NESP55, 1A, XL), are spliced to produce different transcripts, therefore different proteins is made NESP55 maternal allele 1A and XL paternal allele is expressed

44 Disorders affecting the chromatin structure in trans Rubinstein-Taybi syndrome Rett syndrome α-thalassaemia X-linked mental retardation ICF syndrome Methylene tetrahydrofolate reductase deficiency

45 Rubinstein-Taybi syndrome 16q13.3 CBP - CREB-binding protein gene histone acetyltransferase activity Haploinsufficiency of CBP causes decrease in HAT activity Another gene: p300 which also can cause this disease has HAT activity

46 Rubinstein-Taybi syndrome Symptomes: mental retardation broad thumbs and toes facial abnormalities congenital heart defects increased risk of tumor formation

47 Rett syndrome Xq27 MECP2 gene methyl-cpg-binding protein 2 MECP2 binds methylated DNA through its methyl binding domain and interacts with its corepressors Sin3 and HDACs and helps repressing the gene MECP2 regulates splicing of reporter minigenes Lack of functional MECP2 causes altered histone methylation

48 Rett syndrome dominant X-linked postnatal neurodevelopmental disorder symptomes: motor abnormalities, ataxia, seizures, replacement of hand use by purposeless hand-wringing, language regression classified as one of the autism spectrum disorders manifest postnatally, after a period of normal development disruption of social and language development, unusual stereotyped hand or arm movements

49 α-thalasseamia X-linked mental retardation Xq13 ATRX gene chromatin-remodeling protein mutations in ATRX cause down-regulation of the α-globin locus and abnormal methylation of several highly repeated sequences levels of ATRX are tighlty regulated and either decrease and increase cause major neurodevelopmental problems

50 α-thalasseamia X-linked mental symptomes: α thalasseamia retardation moderate to severe mental retardation dysmorphic facial features microcephaly skeletal and genital abnormalities inability to walk

51 ICF I: immundeficiency C: centromeric region instability F: facial anomalies 20q11.2 Loss-of-function mutations in the de novo DNA methyltransferase gene (DNMT3A), which causes the decrease in methylation at centromeric satellites 2 and 3 on the chromosomes 1, 9 and 16

52 ICF Symptomes: immundeficiency, cytogenetic abnormalities craniofacial defects, broad and flat nasal bridge, epicanthal folds high forehead, low-set ears, psychomotor retardation and intestinal dysfunction Immundeficiency is usually severe, and causes premature death during childhood due to respiratoy and intestinal infections

53 MTHFR deficiency 1p36.3 MTHFR gene methylene tetrahydrofolate reductase 677C>T

54 MTHFR deficiency Lack of MTHFR causes the decrease in the level of SAM, which leads to decreased global DNA methylation

55 MTHFR deficiency symptomes: mental retardation hyperhomocysteinemia increased risk of atherosclerosis, neural tube defects and cancer

56 Disorders affecting the chromatin structure in cis αδβ-thalassaemia and δβ-thalasaemia Fragilis X syndrome Facioscapulohumeral distrophy

57 αδβ-thalassaemia and δβ-thalasaemia most common single gene disorder reduced level of one or more of the globin chains of hemoglobin abnormal erythropoesis and profound anaemia deletion in the locus control region of β-globin gene

58 Fragilis X syndrome Xq27.3 FMR1 gene expansion of an unstable CGG repeat at the 5 UTR: Normal: 6-60 Premutation: Full mutation: >200 Aberrantly methylated CGG repeat and decreased histone acetylation patterns leads to loss of expression of FMR1

59 Fragilis X syndrome CGG repeat forms a single and stable hairpin structure, this is cleaved by Dicer resulting a small noncoding RNAs These sncrnss associate with RNA-induced initiator of transcriptional gene silencing (RITS) and recruit DNA de nov methylatransferases and histone methyltransferases to the 5 UTR of FMR1 leading to full methylation of the CGG repeat and transcriptional repression of FMR1

60 Facioscapulohumeral distrophy 4q35 major locus is the subtelomeric region of chromosome 4q35 near D4Z4, a low copy repeat that contains an array of 3.3 kb GC-rich unit number of repeat in healthy human is , while in patients with FSHD is 1-10 contraction of the repeats causes a less repressive chromatin ctate leading to increased transcription of 4q35-qter genes

61 Facioscapulohumeral distrophy autosomal dominant muscular dystrophy symptomes: progressive wasting of the muscles of the face, upper arm and shoulder hearing loss mental retardation seizures

62 Role of epigenetics in our life Conception Aging Cancer Psychiatric diseases

63 Summary Epigenetics influence our lives from the conception till death Underlying causes of psychiatric diseases like schizophrenia and mood disorders Still remain lot to discover

64 THANK YOU FOU YOUR KIND ATTETION!