Establishment of Cell Identity in Drosophila Embryos

from Lodish et al., Molecular Cell Biology, 5th 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

Misexpression of Homeotic Genes Lead to Morphological Abominations

from Lodish et al., Molecular Cell Biology, 5th ed. Fig 15-25

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

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

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)

from Bantignies and Cavalli, Trends Genet. 27, 454 (2011)

Chromatin compaction reinforces PcG silencing and maintains repressive domains

PRC1 and PRC2 Promote Chromatin Compaction

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)

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)

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)

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)

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

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

from Richly et al., BioEssays 32, 669 (2010)

Propagation of H3K27 Methylation

EED2 (ESC) binds H3K27me3 and enhances methylation activity of EZH2 [E(Z)] on a separate histone

EZH2 [E(Z)] methylates H3K27 on adjoining nucleosomes and newly replicated chromatin

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)

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

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

Avy contains an IAP insertion that contains a promoter expressed in all cells

from Jirtle and Skinner, Nature Rev.Genet. 8, 253 (2007)

Avy is a Metastable Epiallele

Avy can be modified in a variable and reversible manner

Methylation status of IAP determines the activity of the ectopic promoter

Avy 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

Maternal Nutrition Alters Gene Expression by Epigenetic Modification

from Jirtle and Skinner, Nature Rev.Genet. 8, 253 (2007)

Feeding of pregnant Avy/a mice with methyl-rich supplements repress the ectopic Avy promoter

Offspring of diet-supplemented mice have brown coat color and methylated IAP

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

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

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

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

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)

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