Epigenetics 04/04/16.

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Epigenetics 04/04/16

A single genome gives rise to distinct cell-types About 210 human cell-types

An example from Andrew Baccerelli; Ode to Joy

Definition Epigenetics refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence. These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. However, there is no change in the underlying DNA sequence of the organism. Non-genetic factors cause the organism's genes to behave (or "express themselves") differently. wikipedia

Epigenetic mechanisms Nucleosome positions Histone modification DNA methylation

Chromatin DNA is packaged into chromatin. Nucleosome is the fundamental unit of chromatin. It wraps 146 bp DNA. The chromatin structure is hierarchical. Felsenfeld and Groudine 2003

Nucleosome and histone modification First layer chromatin structure looks like “beads-on-a-string”. A nucleosome is made of core histone proteins. The amino acids on the N-terminus of histones can be covalently modified. Felsenfeld and Groudine 2003

DNA methylation DNA methylation normally occurs at CpG dinucleotide only and can be inherited during cell-division. Alberts et al. Molecular Biology of the Cell

Aberrant DNA Methylation Pattern in Cancer Irizarry, Feinberg

Transcription regulation ACATGT TF RNA

ChIP-seq analysis

Peak Calling Methods MACS (MACS2) – Liu Lab Peakseq – Gerstein Lab SPP – Park Lab GEM – Gifford Lab

Epigenetic patterns are dynamic Human Umbilical Vein Endothelial Cells: HUVEC; GM12878; lymphoblastoid cell.

Epigenetic patterns are dynamic

Epigenetic patterns are dynamic

Epigenetic patterns are dynamic

Epigenetic patterns are dynamic Aberrant patterns are found in cancer and many other diseases

Enhancers regulate gene expression from a distance

Super-enhancers Whyte et al., Cell 2013

Target super-enhancer in cancer James Bradner

Chromatin state segmentation methods ChromHMM (Ernst&Kellis); Segway (Hoffman&Noble). Both are based on hidden Markov models (HMM). histone mark intensities chromatin state Data are binned. Assumptions Markov property: Independent obs:

Promoter is relatively stable; enhancer is more dynamic Can chromatin state really define cell-identity? Ernst et al., Nature 2011

(Fine, Tishby 1998) Chromatin Domain DO chromHMM

diHMM domain-level state nuc-level state histone mark intensities Each domain-bin corresponds to a block of nuc-bins. nuc-level state histone mark intensities Additional Assumptions Obs is determined only by nuc-level state depends on the domain-level state n Nuc-level transition is domain dependent Domain-level transition can only occur at the end of a block only when i is multiple of block size Marco et al. under review

Comparison with chromHMM (Fine, Tishby 1998) Dom Nuc HHMM chromHMM

Variation of genetic information may predict disease risk wikipedia What is the mechanism?

Noncoding GWAS are enriched with enhancer elements Murrano et al., Science 2012

Identifying disease-relevant cell-types Murrano et al., Science 2012

Source: yewbiotech

BCL11A is a master regulator for globin switch Bauer et al. 2012, Blood

BCL11A erythroid enhancer is required for HbF repression 55 58 62 This modest affect on BCL11A expression and HbF level is just a minimal estimate of the impact of the underlying element. Deletion of the enhancer results in profound loss of BCL11A expression. Hardison and Blobel. Science 2013; Bauer et al. Science 2013

CRISPR/cas9 genome editing

Identifying critical sequences within BCL11A erythroid enhancer Canver et al. Nature 2015

Identifying critical sequences within BCL11A erythroid enhancer

Identifying critical sequences within BCL11A erythroid enhancer

Species divergence at the BCL11A erythroid enhancer Human Mouse essential essential dispensable partially dispensable largely dispensable largely dispensable These results show the

Identifying critical sequences within BCL11A erythroid enhancer

Summary Epigenetics play an important role in gene regulation in development and diseases. Epigenetic regulation provides mechanistic understanding of disease associated genetic variants. Predicted function of regulatory elements can be experimentally tested by CRISPR/cas9 genome-editing.