Epigenetics 12
- 2. Epigenetics at a glance • It is a modern branch of genetics which providing us with a basis for elucidating how heritable changes other than those in DNA sequence can influence phenotypic variation. • Epigenetic gene regulation use reversible modification of DNA &chromatin structure to mediate interaction of the genome with a varity of environmental factor & to generate change pattern of gene expression in response to those factor .
- 3. • Change may be transcription level or mRNA level. • Modified into different genome to become complex & each modified genome called epigenome. • Epigenetic trait is stable both mitotically & meotically heritable phenotype that capable to change gene expression. • Due to epigenetic modification different diseases occur like dibetics,asthma&cancer etc.
- 4. What is intracellular signal to induce epigenome? • Cellular response pathway in epigenetics organized three categories of change. • 1.epigenetor(carcinogen,uv radiation & environmental stress etc). • 2.epigenetic initiators;-it includes protein signal transduction pathway,DNA binding protein,non coding RNA(siRNA). • 3.epigenetic maintainers;-these are not sequence specific in molecular level after modification maintained by DNAmethylase,DNAacetylase&deacetylase.
- 6. Histone modification • It is an important epigenetic mechanism of gene regulation . • Amino acid in N-terminal region of histone can be covalently modified in several ways includes acetylation ,phosphorylation,methylation. • Normally histones are modified by acetylation by histoneacetyl transferase(HAT) open for transcription and deacetylase (HDAC) changing the chromatin closed and silenced the gene making unfevorable for transcription.
- 8. Cntd.. • Other events also includes presence or absence of methyl group on histones. • Methylation in lysine4/27 in H3 causes transcriptional activation while in lysine9 causes transcriptional silencing. • Phosphorylation also occur if serine10 phosphorylation lysine9 methylation inhibited if lysine14 deacetylated methylation of lysine9 is facilited. • This pattern and interaction histone modification called histone code
- 9. RNA interference • During epigenetic regulation small noncoding RNA(siRNA) participate in methylation &histone modification . • siRNA associate with protein to form RNA- induced silencing complex(RISC). • If siRNA perfectly complementary to mRNA then it will cleave mRNA and destroyed then gene silencing effectively occur . • It acts directly preventing trancription factor binding at initiation of transcription TFiiB&RNA polymerase.
- 10. Cntd.. • Another process short RNA molecule can also associate with protein complex to form RNA induced transcriptional silent(RITS) complex &induce formation of facultative heterochromatin that silent gene.
- 11. Different non-coding RNA role in Epigenetics • miRNA-Micro RNA regulate gene expression by blocking translation of specific mRNAs and cause their degradation. siRNA-Turn off gene regulation by directing degradation of selective mRNA. • piRNA-Bind piwi proteins &protect the germ line from transposable element. • lncRNA-long non-coding RNA many which serves as scaffolds ,including X-chromosome inactivation.
- 12. Environment impact &epigenome • Different environment agents like nutrient,chemicals &physical factors has effect on epigenetic changes. • In human it is very difficult to determine the change in epigenome due to environmental &learned behavior but has evidence mainly that agents affect the endocrine system. • For example:- mice coat colour(aghouti &yellow) change due to affect allele.
- 13. Cntd.. • A drug(dietyl still bestol) used in USA several decade for prevent complication of pregnancy and miscarriage. • It would increase high risk of vaginal &breast cancer (female),in male it also affect in neurological and behavioral alteration.
- 14. Epigenetic modification affect behavior • Epigenetic changes include alteration methylation pattern and histone modification may be important component in behavioral change. • Best example in case of honey bee worker. • Worker and queen have same genome worker is sterile but queen fertile . • That epigenetic change occur by royal jelly ,it was discovered by Ryszard Kucharski and colleague in 2008.
- 15. Cntd.. • Royal jelly silence a key gene called Dnmt3 whose product add normally methyl group to DNA with Dnmt3 silencing beeDNA is less methylated that stimulate queen devlopment. • In case human also seen that epigenetic changes in case of neurodegenerative disorders &neuropsychiatric with alter behavioural phenotype.
- 16. Modification due to genome imprinting • Phenomenon of the differential expression of genetic material depending either it is inherited from male or female parents called genome imprinting. • Due to genome imprinting Mendels reciprocal cross do not give identical result. • Due to genome imprinting one Xchromosome remain inactive and expression is balanced. • During gamete formation differential CpG methylation occur which helps in allele specific imprinting & subsequent gene silencing.
- 17. Cntd.. • Different evolutionary point of view different maternal& paternal gene affect in fetal growth (gene conflict hypothesis). • Best example fetal development of human both maternal & paternal IGF2 gene have capable to grow fetus but fetus use paternal IGF2 for best growth. • In maternal case H19 gene expressed and IGF2 gene blocked by CTCF(transcriptional repressor protein)
- 19. Epigenetics and cancer • The relationship between cancer and Epigenetics was first noted in 1980 by Feinberg and Vogelsten who observed in colon cancer cell much lower level of methylation than normal cells derived from same tissue. • Studied that global hypermethylation(CpG) is property of all cancer cell to date that selective hypermethylation& gene silencing. • DNA hypomethylation reverses the inactivation of gene,leading to unrestricted transcription of many gene sets including oncogene&mutation in histone modifying gene seen in some case means dysfunctional HAT&HDAC(Rubenstein-taybi syndrome).
- 20. Cntd.. • Hypomethylation of repetitive sequence leads to transcriptional activation transposable DNA sequences such as LINES(long interspersed nuclear elements) & SINES further increase genomic instability. • Hypermethylation(CpG island) occur that silent tumor supressing gene studied in some cancer case. • Now a day epigenetic therapy also use instead of chemotherapy to express the silent gene.
- 21. Cntd..
- 22. How mutation differ from Epigenetics • Mutation directly affects DNA sequence and occur permanent change but in epigenetic changes temporary time period due to different physical, chemical factors. • In epigenetic changes recovered at time of gamete formation but not in mutation. • Epigenetics is reversible process but mutation is irreversible process.
- 23. THANK YOU