Machine Learning in
Computational Biology
CSC 2431
Lecture 4: Epigenetics
Instructor: Anna Goldenberg
Definitions
Definitions
Histone: cluster of
proteins
Definitions
Histone: cluster of
proteins
Histone + DNA(146-7bp)
= nucleosome
Definitions
Histone: cluster of
proteins
Histone + DNA(146-7bp)
= nucleosome
Definitions
“Epi” – over, above, outer
Epigenetics – stably heritable phenotype
changes in a chromosome without
alterations in the DNA sequence
◦ Histone modifications
◦ DNA methylation
Epigenomics – refers to the study of the
complete set of epigenetic alterations
“Epigenetic code” – epigenetic features
that maintain different phenotypes in
different cells
Epigenetics
Modification to DNA Modification to histones
– DNA methylation (proteins around which DNA is wound)
These modifications change
• during differentiation
• as a response to environment
Example: differentiation
Tightly wound DNA – heterochromatin
Loosely packed, open – euchromatin
Specific epigenetic processes
1. Imprinting (e.g. Angelman syndrome – maternally lost genes on
chr15, paternally silenced)
2. Gene silencing
3. X chromosome inactivation
4. Paramutation (interaction between alleles at a single locus, e.g. maize)
5. Bookmarking (transmitting cellular pattern of expression during mitosis to the
daughter cell)
6. Reprogramming
7. Transvection (interaction of alleles on diff. homologous chromosomes)
8. Maternal effects
9. Progress of carcinogenesis
10. Regulation of histone modifications and heterochromatin
Histone modifications
(posttranslational)
N-termini (tails) are particularly highly modified
Histone modifications
(posttranslational)
N-termini (tails) are particularly highly modified
Acetylation and phosphorylation –
help to open chromatin
Another way to keep chromatin
open
Chromatin remodeling complex
Closed chromatin, gene silencing
Histone and DNA methylation
Epigenetic marks
Epigenetic marks – small chemical tags that sit on top of
chromatin and help instruct it whether to
open or to compact
Red marks – condense the chromatin, prevent the cell from
being able to read the gene, turn the gene off
(silencing)
Green marks – open the chromatin, allowing the gene to be
read
DNA methylation
28 million of CpG regions in the genome
60-80% are heavily methylated
CpG islands (100-2,000bp enriched for
CpG often found at promoters) are un-
methylated across cell types
Modulation of DNA (de-)methylation is
still unknown!
Typical computational analysis
Statistical testing for differential DNA
methylation at a single CpGs and/or large
genomic regions
Correction for multiple hypothesis testing
Ranking based on statistical significance
and effective size
Typical methods for DMR detection
T-test or Wilcoxon rank-sum (Wang et al, Bioinformatics, 2012)
Mixture Models (Wang, Genetic Epidemiology, 2011)
Information theoretic approaches (Zhang et al, NAR, 2011)
Logistic M values (Du et al, BMC Bioinformatics 2010)
Feature Selection (Zhuang et al, BMC Bioinformatics, 2012)
Stratification of t-tests (Chen et al, Bioinformatics, 2012)
Aggregation of genomic regions by type (Poage et al, Cancer
Research, 2012)
Correction for copy-number aberrations (Robinson et al,
Genome Research, 2012)
Linear regression with batch effect removal and peak
detection (Jaffe et al, Int J Epidem, 2012)
C. Bock, Nature Reviews Genetics, v13, October 2012
Computational challenges
Comprehensive mapping of histone modifications,
nucleosome positioning, TF binding and
chromosomal organization per tissue is going to
be done on a smaller scale: detecting signal will be
hard since the sample size will be small
Integrating all the epigenetic data together and
with other types of data
Tools to help identify causes from consequences
of the differences in DNA methylation
New technologies: nanopore sequencing, new
tools to address biases
Functional relevance of the DNA methylation
variants
Example:
Histone modification profiles
Normal vs Cancer
Key findings in cancer
1. Hypermethylation of CpG islands
CpG islands in the promoters of tumor
suppressor genes are methylated
Tumor suppressor genes are inactivated
Tumors are able to grow
2. General Hypomethylation
Interesting case
Glioblastoma Multiforme
Sturm et al, Cancer Cell, 2012
Interesting case
Glioblastoma Multiforme
Sturm et al, Cancer Cell, 2012
IDH1
IHD1/2 mutations inhibit both histone and DNA demethylation and alter
epigenetic regulation
Epigenetics Databases
MethDB 5,382 methylation patterns, 48 species, 1151
individuals, 198 tissues and cell lines, 79 phenotypes
PubMeth 5000+ records on methylated genes in cancers
REBASE 22,000+ DNA methyltransferases genes derived
from GenBank
MeInfoText methylation information across 205 human
cancer types
MethPrimerDB 259 primer sets from human, mouse and rat
for DNA methliation analysis
ChromDB 9,341 chromatin association proteins
The Histone Database – 254 sequences from histone H1,
383 from H2, 311 from H2B, 1043 from histone H3 and 198
from H4
Epigenetic Roadmap (NIH project)
Papers
DNA methylation across tissues:
Ma, B., Wilker, E. H., Willis-Owen, S. A., Byun, H. M., Wong, K. C.,
Motta,V., ... & Liang, L. (2014). Predicting DNA methylation level
across human tissues. Nucleic acids research, 42(6), 3515-3528.
Inferring chromatin states
Ernst, Jason, and Manolis Kellis. "Discovery and characterization of
chromatin states for systematic annotation of the human genome."
Nature biotechnology 28.8 (2010): 817-825.
