1. Establishment of Cell Identity in Drosophila Embryos from Lodish et al., Molecular Cell Biology, 5 th ed. Fig 15-24 Segment identity is established by sequential spatially-localized expression of specific genes Regulatory genes are expressed transiently Transcriptional memory is maintained throughout development

2. Misexpression of Homeotic Genes Lead to Morphological Abominations from Lodish et al., Molecular Cell Biology, 5 th ed. Fig 15-25

3. Polycomb-group Proteins Maintains a silenced state Trithorax-group Proteins Maintains an active state Counteracts the action of PcG proteins Memory system composed of PcG and trxG complexes is linked to the histone code Prevents changes in cell identity by preserving transcription patterns Polycomb and Trithorax Complexes Chromatin is altered in a heritable manner Prevents chromatin remodelling

4. Polycomb Group Complexes on Chromatin in Drosophila from Bantignies and Cavalli, Trends Genet. 27, 454 (2011) PcG proteins are recruited to Polycomb response elements E(z) of PRC2 trimethylates H3K27 Pc of PRC1 is recruited to H3K27me3 dRING on PRC1 ubiquitylates H2AK119 H3K27me3 is segregated to both daughter chromosomes to maintain repression

5. Recruitment of PRC2 to Chromatin in Mammals PRC2 can be recruited to a PRE by transcription factors or long ncRNAs from Morey and Helin, Trends Biochem.Sci. 35, 323 (2010)

6. from Bantignies and Cavalli, Trends Genet. 27, 454 (2011) Chromatin compaction reinforces PcG silencing and maintains repressive domains PRC1 and PRC2 Promote Chromatin Compaction

7. Co-suppression PcG complexes interact in trans Increase in gene copy number results in decreased expression Dependent on PcG genes from Pirrotta, Cell 93, 333 (1998)

8. Formation of a Repressive Chromatin Hub PREs and promoters make contact and form chromatin loops CTCF and cohesin stabilize loops Chromatin loops are enriched in visible PcG bodies Loops could reinforce the memory of the silenced state from Bantignies and Cavalli, Trends Genet. 27, 454 (2011)

9. Chromosome Kissing PcG proteins mediate long- range chromatin contacts Distant complexes of chromosome loops can interact with eath other from Bantignies and Cavalli, Trends Genet. 27, 454 (2011)

10. Segment-specific Localization of Genes in PcG Bodies Hox genes are organized in two clusters in Drosophila PcG bodies are subdomains of the nucleus that correlate with gene repression Antp and AbdB genes are silenced in the head (B) Antp and Ubx are silenced in the posterior (C) PcG genes maintain the regional identity of segments by repressing Hox genes in specific regions from Hodgson and Brock, Cell 144, 170 (2011)

11. HOTAIR Represses Genes in trans HOTAIR is a ncRNA expressed by the HOXC locus HOTAIR acts in trans to repress the HOXD locus on a different chromosome HOTAIR associates with PRC2 and recruits the complex to the HOXD locus

12. ncRNA Recruits PRC2 to Control Flowering from Heo and Sung, Epigenetics 6, 433 (2011) Vernalization – Many plants flower in spring after prolonged low temperatures FLC2 represses genes required for flowering COLDAIR is a ncRNA that is induced by prolonged low temperatures COLDAIR acts in cis and recruits PRC2, promotes H3K27me3, and stably represses FLC

13. from Richly et al., BioEssays 32, 669 (2010) Propagation of H3K27 Methylation EED2 binds H3K27me3 EED2 binding stimulates PRC2 activity EZH2 methylates H3K27 on adjoining nucleosomes

14. Demethylation of H3K27me3 Promotes Gene Activation PRC2 is recruited to H3K27me3 to mediate gene repression UTX and JMJD3 are recruited to Hox promoters and reverse repression Change in cell fate is mediated by H3K27 demethylation and H3K4 methylation, whose activities are present in the same complex from Rivenbark and Strahl, Science 318, 403 (2007)

15. Trithorax-group Protein Mechanism of Action TrxG proteins maintain an active transcriptional state TrxG proteins modify histones, remodel chromatin, and oppose PcG-mediated gene silencing

16. from Dolinoy, Nutr.Rev. 22 (Suppl. 1), S7 (2008) The Viable Yellow Agouti Locus Agouti promotes yellow pigment formation on black hair shaft Wild-type mice have brown fur due to Agouti expression from hair cell-specific promoter A vy contains an IAP insertion that contains a promoter expressed in all cells

17. from Jirtle and Skinner, Nature Rev.Genet. 8, 253 (2007) A vy is a Metastable Epiallele A vy can be modified in a variable and reversible manner Methylation status of IAP determines the activity of the ectopic promoter A vy can be used as an epigenetic biosensor to study the nutritional and environmental influences on the fetal epigenome Ectopic Agouti expression causes yellow fur, obesity, diabetes and tumorigenesis

18. Maternal Nutrition Alters Gene Expression by Epigenetic Modification from Jirtle and Skinner, Nature Rev.Genet. 8, 253 (2007) Feeding of pregnant A vy /a mice with methyl-rich supplements repress the ectopic A vy promoter Offspring of diet-supplemented mice have brown coat color and methylated IAP

19. Progression of Epigenetic Changes in IUGR Rats Pdx1 is a transcription factor necessary for  -cell function from Pinney and Simmons, Trends Endocrinol.Metab. 21, 223 (2009) Intrauterine growth restriction recruits histone deacetylases that prevents USF-1 binding Altered histone methylation reinforces Pdx1 repression Recruitment of DNMT3A locks Pdx1 in a silent state The result is defective glucose homeostasis

21. Somatic Cell Reprogramming from Cedar and Bergman, Nature Rev.Genet. 10, 295 (2009) Pleuripotency genes in somatic cells have methylated CpG islands Epigenetic marks must be reset to generate induced pleuripotent stem (iPS) cells Repressive histone methylation marks must be removed, followed by removal of DNA methylation which activates the gene

22. Brg1, a SWI/SNF component, is activated by cardiac stress Brg1 suppresses expression of a CKI to promote myocyte proliferation Brg1 forms a complex with HDAC and PARP and triggers a shift from  -myosin heavy chain expression to  -myosin heavy chain expression Epigenetics and Heart Failure from Hang et al., Nature 466, 62 (2010) Brg1 promotes reprogramming to an embryonic state of transcription

23. Epigenetic Modifications May Drive Cognitive Decline from Sweatt, Science 328, 701 (2010) Chromatin remodeling in the hippocampus is necessary for stabilizing long term memories Aged mice have lower H4K12 acetylation HDAC inhibitor restores H4K12 acetylation and improved memory function

24. Prion Epigenetics Prions template conformational conversion of other molecules of the same protein Prions are disseminated to daughter cells during cell division Prions are formed through an oligomeric nucleus, and the elongating polymer is severed by protein remodeling factors from Halfmann and Lindquist, Science 330, 629 (2010)

25. Stress Accelerates Prion Appearance from Halfmann and Lindquist, Science 330, 629 (2010) Prion-free cells are adapted to environment 1, but poorly adapted to environment 2 Prion formation and disappearance provide fitness advantages in different environments Abrupt changes have consequences for protein folding Prions connect environmental conditions to acquisition and inheritance of new traits