Epigenetics and Diseases

Question 1

Snrpn cluster is crucial for which disease?

Answer 1

Angelman and Prader-Willi syndromes

Question 2

ASOs ?

Answer 2

Antisense Oligonucleotides (small synthetic RNA molecules that
binds target RNA), used to treat genetic disorders like Angelman. ASO binding would result in dsRNA which would then be digested by RNAseH

Question 3

treatment for Angelman (still in trial)?

Answer 3

ASOs that bind to snrpn/snoRNA => degradation, preventing them from assisting the as-UBE3A exrpession and thus allowing for the normal UBE3A to be expressed.

Question 4

chromatin remodellers?

Answer 4

dynamical modification of chromatin structure, (e.g.

Question 5

What is distinct feature of Genetic Disorders affecting Chromatin Structure

Answer 5

they have a trans effect, they secondarily alter chromatin structure in various places throughout the genome and thus have very complex phenotypes

Question 6

Examples of Chromatin Structure Disease with a trans effect

Answer 6

Rett Syndrome (RTT), Kabuki syndrome, ATRX = Alpha-thalassemia X-linked intellectual disability syndrome

Question 7

Examples of Chromatin Structure Disorders with a cis effect

Answer 7

Thalassemia: abnormal hemoglobin production due to deletions of the
locus control region (LCR)
* Fragile-X-syndrome (FXS)
* Facioscapulohumeral dystrophy (FSHD)

Question 8

1:10.000 live female births.
 Symptoms (age of 12-18 months):
loss of speech, microcephaly, autism,
ataxia, stereotypic hand movements,
seizures and breathing problems.
 There are no curative therapies for this disease
 Caused by heterozygous mutations in the
X-linked MECP2 gene

What is the following disease?

Answer 8

Rett Syndrome (RTT)

Question 9

What does a dysfunctional in KMT2D (H3K4me) lead to?

Answer 9

Type 1 Kabuki syndrome

Question 10

What does a dysfunctional KDM6A lead to?

Answer 10

Type 2 Kabuki syndrome

Question 11

Example of dysfunctional remodeller caused syndrome?

Answer 11

ATRX, ALpha-Thalasemia X-linked intelectual deficiency syndrome

Question 12

MeCPB2 function

Answer 12

MeCPB2 (methyl CpG binding protein 2) generally binds to symmetrycally methylated CpG with its Methyl-CpG binding domain (MBD) while with its NID (NcOR/SMRT Interaction Domain) recruits HDACs adn chromatin remodellers => transcriptional repression.

However MeCPB2 binds differently in multiple sites in the genome so in addition it is also serves role in transcriptional activation, loop formation and compaction

Question 13

Why the phenotype of RTT is so complex?

Answer 13

MeCPB has very complex binding sites with drastically different function all throughout the genome

Question 14

One of the most common causes of inherited intellectual disability
* X-linked dominant disorder (females milder symptoms)
* Males have intellectual disability, macroorchidism, connective tissue abnormalities
(hyperextensibility of joints and large ears)
* Gene responsible is FMR1 -> FMRP, part of RNA-induced silencing complex)

Answer 14

Fragile-X Syndrome

Question 15

Cause of Fragile X syndrome

Answer 15

Expansion of an unstable noncoding CGG repeat at the 5′-UTR (untranslated region)
of the FMR1 gene

=> Methylation of CpG island in 5′-UTR + decreased Histone acetylation => silencing FMR1

Question 16

Autosomal dominant muscular dystrophy
(progressive wasting of the muscles of the face,
upper arm, and shoulder).
* FSHD1 in the subtelomeric region of chr 4, it contains D4Z4 macrosatellite
repeats (11–150 units on normal chr & 1–10 units on FSHD chr)
* First documented activating ncRNA associated with human disease
(DBE-T long noncoding RNA)
* DBE-T RNA knockdown is the best therapeutic target

Answer 16

Facioscapulohumeral Dystrophy (FSHD)

Question 17

Cause of FSHD

Answer 17

FSHD repeat contraction, so opposite of what happens in FXS.

Contraction leads to more expression and activating markers whic

Question 18

Why the epigenetics of cancer is particularly crucial for treatment?

Answer 18

epigenetic changes are reversible unlike genetic ones

Question 19

Best biomarker/predictor of cancer progression

Answer 19

DNA methylation

Question 20

Typical DNAm patterns in cancer

Answer 20

Hypermethylation
 Inactivation of tumor suppressor genes
 Inactivation of DNA repair genes
(CpG island rich promoters)

and
Hypomethylation
 Retrotransposon activation (repeats)
 Genomic instability
 Oncogene activation (CpG poor promoters)
e.g. R-RAS in gastric cancers

Question 21

Knudson Hypothesis

Answer 21

cancer results from multiple hits

The Knudson hypothesis, also known as the two-hit hypothesis, is the hypothesis that most tumor suppressor genes require both alleles to be inactivated, either through mutations or through epigenetic silencing, to cause a phenotypic change.[1]
(wiki)

Question 22

What does a hyopermethylated promotor tell us about cancer prognosis?

Answer 22

Mosto often bad news but for some cancer types it could mean good prognosis

Question 23

Tumour suppressor hypermethylation is more common than mutations. True of False

Answer 23

True
*
- Mitotically heritable
- Epimutations are rapidly selected for

Question 24

Biomarker

Answer 24

biological molecule found in blood, other body
fluids, or tissues that is a sign of a normal or abnormal process,
or of a condition or disease.

Question 25

Single gene examples of hypermethylation:

Answer 25

RB in retinoblastoma (frequently inheritable)
MLH1 (mismatch repair) in colorectal and endometrial cancers
BRCA1 (homologous recombination repair pathway) in breast cancer
MGMT (direct repair) in gliomas (brain cancer) and colorectal tumours

Question 26

DNAm vs histone modifications as cancer biomarkers

Answer 26

HMs are less representative of gene expression than methylation and there are
limitations of ways to analyse PTMs.

They can still be prognostic tho.

Question 27

What is a characteristic change of nuclear architecture in prostate cancer?

Answer 27

Increased number of TADs / smaller size due to more frequent CTCF binding, cancer-specific TADs boundaries

Question 28

DNMT inhibitors for cancert treatment

Answer 28

Vidaza (5-azacytidine), Decitabine (5-aza-2’-deoxycytidine)
Nucleoside analogues, irreversibly bind DNMTs, after they are incorporated into
DNA, therefore replication-dependent
* Lack of specificity due to their mechanism of action, few side effects

Question 29

Example of altered ncRNA in cancer

Answer 29

HOTAIR,

HOTAIR overexpressed in breast cancer, particularly associated with metastasis
- In vitro overexpression retargets PRC2 to other sites, gene expression like
embryonic fibroblast.
- Poor prognosis (breast, esophageal,
colon and liver cancer)

Question 30

HDAC inhibitors

Answer 30

Transcriptional activating effect. Presumed mode of work is through activation of
tumour suppressor genes, although unclear. Not selective.
* Might be ’’dirtier’’ than other inhibitors because they target other protein
deacetylateses, not only histone deacetylases
* Effective against lymphoid malignancies

Question 31

biggest drawbacks of epigenetic therapy

Answer 31

Drug do not perform targeted (locus-specific) modification of the chromatin
* Rarely patients are stratified according to their genetic or epigenetic profiles