EPIGENOMICS EPIGENETICS

Afiono Agung Prasetyo

Satellite DNA
Satellite DNA comprises very long arrays of
tandem repeats typically 100 kb to several
megabases in size, the repeat unit length varying
between 5 and 171 bp.
Minisatellite DNA arrays are of intermediate
size and typically span between 100 bp and 20
kb, with each repeat unit between 6 and 100 bp
in length.
Microsatellite DNA comprises short arrays less
than 100 bp in size, made up of simple tandem
repeats 16 bp in length.

forensic

EPIGENOME
The eukaryotic genome is packaged into nucleosomes,
which form the basal unit of chromatin, the physiological
form of DNA within the nucleus. Apart from its function in
compacting the immense nuclear DNA molecules,
chromatin also serves as a platform onto which multiple
signalling pathways converge to cooperate in
determining the expression status of mRNAs and other
(non-coding) RNA molecules.
Epigenetic profile analysis aims to determine what
changes on the nucleosomes cooperate to establish and
maintain DNA sequence-independent heritable traits
such as those determining cell identity.

CpG-island
Roughly half of the human promoters are
located within a CpG-island, a region in
which the CpG dinucleotide motif is
overrepresented relative to the average
genome
cytosine methylation, occurring at position
5 of the cytosine pyrimidine ring in CpG
dinucleotides

 Epigenetic processes are essential for normal

cellular development and differentiation, and allow
the regulation of gene function through nonmutagenic mechanisms.
The methylation of the CpG sites, overrepresented in CpG-islands in the promoter
regulatory regions of many genes, disrupts the
binding of transcription factors and attracts
methyl-binding proteins that initiate chromatin
compaction and gene silencing.
Histone modification, another epigenetic
mechanism mediating gene expression, affects
chromatin organization via the processes of
histone acetylation, histone methylation, and
histone phosphorylation.

Methyl-DNA binding proteins

are mostly part of multiprotein complexes that
contain chromatin modifying
activity represented by
histone-deacetylases
(HDACs) and chromatin
remodelers

Primary Defects in DNA

Methylation and Their Diseases
abnormal DNA-methylation is found in many genes in cancer and
other conditions
The proteins that are known to methylate DNA are DNMT1, DNMT3A
and DNMT3B.
Five proteins interact with methylated C (me-C) namely MBD1,
MBD2, MBD3, MBD4 and MeCP2.
These processes are fundamental for the function of the cell, and it is
surprising that mutations in these proteins show manifestations in
only selected cell types.
Mutations in both alleles of the gene DNMT3B lead to a recognizable
syndrome of severe, often lethal immunodeficiency, centromeric
instability and facial anomalies (ICF) syndrome i.e. it is inherited as
an autosomal recessive trait.
Cytogenetic analysis show severe disturbances of the
pericentromeric regions of chromosomes 1, 9 and 16, known to
contain satellite DNA. Most patients with this phenotype have been
shown to harbour mutations in the DNA methyltransferase sequence
motifs of DNMT3B and a recognisable lack of de novo methylation of
the pericentric heterochromatic repeats.

Defects in Histones, Histone Modifying

Enzymes and General Transcription Factors
and Their Diseases
Mutations in these proteins most often result in malignant
transformation including both solid tumors and leukemia.
Another common result is a syndrome, i.e. a mixture of
clinical symptoms from different cells and tissues, which is
logical since basic machineries are perturbed.
Mutations in genes encoding two histones have been
significantly associated with cancer: HIST1H1B with
colorectal cancer and HIST1H4I with non-Hodgkins
Lymphoma (NHL).
There are several covalent modifications to histones that are
associated to different cellular processes. Methylation and
acetylation of various residues of H3 and H4 are found in
distinct regions of the genome, and there are specific
enzymes that add or remove these marks. Mutations are
found in genes performing all these processes and the most
common outcome is cancer.

Constitutional Mutations of Transcription

Factors and Disease
2,000 genes for proteins involved in the gene regulatory
machinery.
there are few proteins involved in DNA methylation, and a
slightly higher number involved in the maintenance of
core chromatin proteins.
The high number of genes makes them a large target for
mutations and their diverse functions result in a wide range
of clinical manifestations.
TFs are essential for a normal embryonal development and
consequently mutations in many TFs cause congenital
syndromes.
Today mutations in >133 genes encoding TFs are known
to cause syndromes, autosomal dominant, autosomal
recessive and X-linked recessive diseases, that each are
relatively rare.

Mutated transcription factors in

common diseases:
GATA binding protein 2 (GATA2): early onset coronary artery
disease
Hepatocyte nuclear factor 4 alpha (HNF4A): maturity-onset
diabetes of the young (MODY) type 1
Insulin promoter factor 1 (IPF1): pancreatic agenesis, MODY
4, type 2 diabetes
Interferon regulatory factor 5 (IRF5):SLE
Kruppel-like factor 11 (KLF11):MODY 7, type 2 diabetes
MADS box transcription enhancer factor 2, polypeptide A
(MEF2A):coronary artery disease, myocardial infarction
MLX-interacting protein-like (MLXIPL):plasma triglycerides
Neurogenic differentiation 1 (NEUROD1):MODY type 6
Peroxisome proliferative activated receptor, gamma
(PPARG):obesity, modifier type 2 diabetes, familial partial
lipodystrophy, follicular thyroid ca

EPIGENETICS & CANCER

DNA methylation
Genomic hypomethylation increases the
probability of genomic rearrangements
through chromosomal instability and also
contributes to oncogene activation that can
lead to the development of cancer.
Silencing of genes through hypermethylation
can contribute to many of the hallmarks of
cancer including evading apoptosis,
insensitivity to antigrowth signals, sustained
angiogenesis, limitless replicative potential,
and tissue evasion and metastasis

HISTONE ALTERATIONS

Many genes that are altered in cancer

cells are the result of histone
modifications
hTERT, c-Myc, p21, p53, Sp1, Mad,
Mnt

OTHER EPIGENETIC
PROCESSES ON CANCER
Noncoding RNAs
Chromosome position effect
can affect DNA methylation
Chromatin remodeling in cancer
a combination of chromatin modifying and remodeling activities
contribute to the initiation or maintenance of altered gene
expression patterns in cancer.
poly-ADP-ribosylation (PAR): a posttranslational modification of
proteins
PAR can lead to ADP-ribose polymer adducts on histone
proteins thereby contributing to aberrations of gene expression
in cancer.
The polycomb group (PcG) proteins also influence chromatin and
can maintain gene silencing through covalent modification of
histone tails.
high levels in various cancers and important in cancer stem
cells.

Schizophrenia (SZ) and bipolar

disorder (BD)
2% of the population
hard to explain using traditional DNA- and environmentbased mechanisms.
For example, despite sharing the same DNA sequence, the
concordance rate between monozygotic (MZ) twins for major
psychosis is far from 100%: between 41 and 65% for SZ and
about 60% for BD.
a fluctuating disease course with periods of remission and
relapse, sexual dimorphism, peaks of susceptibility to disease
coinciding with major hormonal rearrangements, and parent-oforigin effects. These observations have led to speculation about
the importance of epigenetic factors in mediating susceptibility to
both SZ and BD.

(ARVCF, BDNF, COMT, DRD4, DTNBP1, GAD1,

GRIN2B, MTHFR, NRG1, and RELN). Little evidence
was found to suggest that DNA methylation in these
genes is associated with either SZ or BD.