Unit 6. Epigenetics, a Presentation from Universidad Europea

UNIT 6. EPIGENETICS

1. DNA Methylation
2. Histone modification
3. Non-coding RNA
4. Development
5. X chromosome inactivation
6. Genomic imprinting
7. Transgenerational epigenetic changes

QUESTION EVERYTHING
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Universidad
EuropeaEpigenetics
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TEDEd

WHAT IS EPIGENETICS?

https://www.youtube.com/watch?v= aAhcNimvhcEpigenetics
CS
Me
B
Me
Me
M
Histone tails
Histones
Chromosome
Adapted from Jane Qiu, Nature 441, 143-145(11 May 2006)
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Genetic modifications that affect
gene activity, without changing the
DNA sequence.
Main mechanisms:
Non-coding RNAs
DNA methylation
Histone modification
Chromatin and histones can have chemical modifications that
change the degrees to which genes are turned on and off. Certain
epigenetic modifications may be passed on from parent cell to
daughter cell during cell division or from one generation to the next.1.

DNA Methylation & Histone Modification

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a
b
Active chromatin
Methyl-lysine
activating
Acetyl-
lysine
Methylated
CpG
Unmethylated
CpG
CpG
€> -
Silenced gene
Active gene
Inactive chromatin
Histone modifications
Nucleosome
Histone tail
Repressed gene
Expressed gene

• Active chromatin (euchromatin) is an
  open structure that is accessible to
  nuclear factors (so it can be "read" or
  translated into mRNA)
• Inactive chromatin
  (heterochromatin) is a condensed
  structure that is not accessible to
  nuclear factors (so it can not be "read")
• DNA methylation in Cytosine-Guanine dinucleotides in gene promoters
  is associated with inactive, condensed state of chromatin.
  Approximately 70% of human genes are
  linked to promoters high in CpG.
• Different combination of histone chemical modifications
  regulate chromatin structure and transcriptional status.
• Acetylation (activates expression)
• Methylation
• Others
  Methyl-lysine
  inactivating
  Methyl
  CpG
  *
  DNA methylationDNA Methylation & Histone Modification
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  Gene
  Histone tail
  .
  Histone
  Methyl group
  DNA inaccessible, gene inactive
  Histone tail
  Acetyl group
  DNA accessible, gene active
  Methylation of DNA and
  histones causes nucleosomes to
  pack tightly together.
  Transcription factors cannot
  bind the DNA and genes are
  silenced
  Histone acetylation results in
  loose packing of nucleosomes.
  Transcription factors can bind
  the DNA and genes can be
  expressed.Epigenetics
  Experiment 1.
  Compact
  DNA
  Methyl Tag
  Acetyl Tag
  Loose
  Green Fluorescent Protein
  (GFP)
  ueDo You
  Remember?

TRANSCRIPTION

Synthesis of mRNA from a strand of DNA
. The reaction is catalysed by the RNA polymerase enzyme, that binds the promoter
(region of DNA to which the enzyme binds to start the transcription).
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L
ATGATCTCGTAA
TACTAGAGCATT
1
DNA
ATGATCTCGTAA
AUGAUCU MRNA
TACTAGAGCATT
J
DNA
mRNA
AUGAUCUCGUAA
Enhancer
+ Activators
Transcription Factors
Promoter
Gene
RNA Polymerase II
Enhancer: A regulatory DNA sequence that, when bound by specific
proteins called transcription factors, enhances the transcription of an
associated gene
https://sites.google.com/site/biologiatercerp/evaluacionDNA Methylation & Histone Modification
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EPIGENETIC MECHANISMS

HEALTH ENDPOINTS

are affected by these factors and processes:

• Cancer
• Development (in utero, childhood)
• Autoimmune disease
• Environmental chemicals
• Mental disorders
• Drugs/Pharmaceuticals
• Diabetes
• Aging
• Diet
  CHROMATIN
  EPIGENETIC
  FACTOR
  CHROMOSOME
  METHYL GROUP
  DNA
  DNA methylation
  Methyl group (an epigenetic factor found
  in some dietary sources) can tag DNA
  and activate or repress genes.
  GENE
  HISTONE TAIL
  HISTONE
  Histones are proteins around which
  DNA can wind for compaction and
  gene regulation.
  DNA inaccessible, gene inactive
  HISTONE TAIL
  DNA accessible, gene active
  Histone modification
  The binding of epigenetic factors to histone "tails"
  alters the extent to which DNA is wrapped around
  histones and the availability of genes in the DNA
  to be activated.RNA interference (non-coding RNA)
  ue
  Non-coding RNA (ncRNA) is a RNA molecule that is transcribed from DNA but not translated
  into proteins. Non-coding RNA is involved In gene silencing processes. Examples:
• Short interfering RNAs (siRNA)
  They cause the degradation of a complementary mRNA blocking the translation.
• Micro RNAs (miRNA)
  They also bind to complementary mRNAs and they can inhibit translation or cause degradation.
• Piwi-interacting RNAs (piRNA)
  Supress activation of transposable elements (Transposons or "jumping" genes)
• Long non-coding RNA
  miRNA
  miRNA-
  protein
  complex
  mRNA
  OR
  mRNA degraded
  Translation blockedEpigenetics
  ue

Changes in DNA methylation during Embryonic Stem Cells (ES) differentiation

Pluripotent Stem Cells have the capacity to differentiate
into all three germ layers: ectoderm, mesoderm and
endoderm. And these will generate all the terminal lines
of differentiated cells (e.g, neurons, skeletal muscle cells,
skin cells .... ).

• All the cells have the same DNA sequence ...
• But the expression patterns of the genome are
  different due to epigenetic regulation.
  ES Cells
  Self-renewal circuit
  Differentiation
  e.g. Embryogenesis
  Ectoderm
  Endoderm
  Mesoderm
  Neural
  Differentiation
  Mammary
  Development
  Monn et al., 2008. Mol CellEpigenetics
  ue

Changes in DNA methylation during Embryonic Stem Cells (ES) differentiation into neurons

Experiment 1.
Differentiation
ES cell
Neuron
5mC (MeDIP)
7
DNA methylation
(log2 IP/Input)
0.5-
0
*** average
-0.5
ES cell
NP
Neuron
n = 277
(81%)
n = 59
(17%)
n= 7
(2%)
Mohn et al., 2008. Mol Cell
DNA methylation dynamically
increases as the cell differentiates,
to reinforce cell-type specific gene
expression.Epigenetics

X chromosome inactivation: dosage compensation

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• Prevents doubling of sex-linked gene products
  Although females have two X chromosomes, female cells do not produce twice as much of the proteins
  encoded by genes on the X chromosome. Instead, one of the X chromosomes in females is inactivated
  early in embryonic development, shortly after the embryo's sex is determined.
  Which X chromosome is inactivated in females varies randomly from cell to cell.
  Two cell populations
  in adult cat:
  Early embryo:
  X chromosomes
  Active X
  Inactive X
  Orange
  fur
  Cell division
  and X chromosome
  inactivation
  Allele for
  orange fur
  Allele for
  black fur
  Inactive X
  Active X
  D
  Black
  fur
  Genetic mosaics:
  Females are genetic mosaics:
  Their individual cells may
  express different alleles,
  depending on which
  chromosome is inactivated.Epigenetics

Transgenerational transfer of epigenetic changes

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Evidence 2.
Dutch Hunger Winter

• Man-made famine (1944-1945, Netherlands)
• The population was forced to live on rations of 400-
  800 calories per day for three months
  . It was imposed on a previously well-nourished
  population.
  Humans exposed at any stage in utero showed a
  higher risk for type 2 diabetes and heart disease as
  adults.
  Children whose parents were in utero during the
  famine were heavier at birth/adult life.
  FO
  Nutrient
  starvation
  Famine
  Cytoplasm
  Autophagy induction
  Nucleus
  Autophagy-induced chromatin modifications
  F1
  Transgenerational
  epigenetic inheritance
  DNA Methylation
  histone posttranslational modifications
  F2
  epigenetic
  autophagy
  memory
  epigenetic
  autophagy
  memory
  e.g. DNA methylation*
  at Autophagy-related
  genes
  H3K4me3*, H3K9me3*, H3R17me2,
  H3K27me3*/ac, H3K56ac, H4K16ac,
  H4K20me3
  * involved with transgenerational epigenetic inheritance
  Impact on health span
  and longevity
  Video
  Fetal and prepubertal childhood exposure to famine is
  linked to transgenerational effects on health and
  longevity in offspring due to epigenetic changes
  caused by malnutrition.Epigenetics

Child adverse events & (mental) health

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Evidence 3.
Published in final edited form as: Dev Psychopathol. 2016 Oct 3;28(4 Pt 2):1319-1331. doi:
10.1017/S0954579416000870 ₡Z
Childhood Adversity and Epigenetic Regulation of Glucocorticoid
Signaling Genes: Associations in Children and Adults
Audrey R Tyrka 1,2, Kathryn K Ridout 1,2, Stephanie H Parade 2,3
Author information > Article notes > Copyright and License information
PMCID: PMC5330387 NIHMSID: NIHMS849422 PMID: 27691985
Maltreatment
Changes in gene
expression
DOS
Epigenetic
changes
Proposed alterations in
affective and behavioral
phenotypes
Pup
A pup that is raised by an
anxious, low-nurturing mother
becomes an anxious adult.
A pup that is raised by a
relaxed, high-nurturing mother
becomes a relaxed adult.Epigenetics
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Front Mol Neurosci. 2023; 16: 1099284.
Published online 2023 Apr 13. doi: 10.3389/fnmol.2023.1099284
PMCID: PMC10133561
PMID: 37122626
Neurobiological mechanisms involved in maternal deprivation-induced
behaviours relevant to psychiatric disorders
Natália Cristina Zanta, + Nadyme Assad, t and Deborah Suchecki
*
Epigenetic
mechanisms
Emotional environment
Maternal deprivation (early postnatal stress)
Higher risk to:

• Depression
• Mood disorders
• Schizophrenia
• PTSD, etc ..
  Behavioural outcomes
  Alterations on:
• Stress-related hormones (HPA),
• Neurogenesis, Neurotransmitter/
  neuro-modulatory systems (such
  reward circuits)
• Neuro-inflammation
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10133
  561/table/tab1/?report=objectonlyEpigenetics, nature vs. nurture
  ue
  THANKS,
  I'M ALIVE!
  WHO AM I?
  WHY AMI?
  + EVZ
  IT'S
  LATER
  EVEN LATER
  ROUND!
  3
  600
  EARLY EXPLAINATIONS
  SCIENCE EMERGES
  THEIR GENES ARE IDENTICAL
  SO IT MUST BE THEIR
  SEPARATE ENVIRONMENTS
  THAT HAVE MADE THEM SO
  DIFFERENT, RIGHT?
  EPIGENETICS
  NURTURE
  NATURE
  OH
  A POPULAR THEORY
  THAT IT IS THE
  STUFF AROUND US
  - LIKE OUR UPBRINGING.
  THAT MAKES US US
  DAR
  10
  0
  IT ALL STARTED
  WITH MY MOTHER
  FREUD
  GENES!
  AN UNCHANGEABLE
  BLUEPRINT, IN YOU
  FROM BIRTH DECIDES
  EVERYTHING .
  https://www.youtube.com/watch?v=k50yMwEOWGU
  04:55
  TIM
  LEANE
  1
  REWIND A BIT IN TIMEEpigenetics, the current perspective
  ue
  Genes
  Behaviour
  Environment
  Genes
  Behaviour
  EnvironmentEpigenetics, the current perspective
  ue
  M
  NO TRANSCRIBING!
  M
  Epigenetics
  with the Amoeba Sisters
  ON
  Gene Expression and Regulation
  with the Amoeba SistersOh , hey ! How have
  you been, methyl?
  I have this great
  idea for a protein
  I want to make
  It's gonna be so
  Cool - just you wait
  and see . It'll have
  all these amino
  acids and a highly
  complex structure
  that will make it -
  Shhh.no.
  ue
  Another gene silenced.
  Thank you!
  QUESTION EVERYTHING