Course Title:

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Course Title Epigenetics
Principle Lecturer Professor Bao Liu
(??) E-mail baoliu_at_nenu.edu.cn Homepage
http//www.nenu.edu.cn/professor/pro/show.php?id1
38 Other Lecturers Dr. Ningning Wang(???) Dr.
Jinsong Pang (???) Dr. Yu Zhang (??)
Key Laboratory of Molecular Epigenetics of MOE,
Northeast Normal University, Changchun, 130024,
China
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Course Title Epigenetics
Lecture Titles Lecture 1 General Overview and
History of Epigenetics Lecture 2 DNA
methylation Lecture 3 Alteration in DNA
methylation and its transgenerational
inheritance Lecture 4 DNA methylation and genome
stability Lecture 5 Histone modifications Lectur
e 6 Noncoding small RNAs Lecture 7 Epigenetic
control of gene expression Lecture 8 Epigenetic
variation in genome evolution and crop
improvement Lecture 9 Epigenetics and human
health Lecture 10 Summary
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Course Title Epigenetics
Lecture Titles Lecture 1 General Overview and
History of Epigenetics Lecture 2 DNA
methylation Lecture 3 Alteration in DNA
methylation and its transgenerational
inheritance Lecture 4 DNA methylation and genome
stability Lecture 5 Histone modifications Lectur
e 6 Noncoding small RNAs Lecture 7 Epigenetic
control of gene expression Lecture 8 Epigenetic
variation in genome evolution and crop
improvement Lecture 9 Epigenetics and human
health Lecture 10 Summary
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Father of Genetics, discovered the basic laws of
heredity.
Gregor Mendel (1822-1884)
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Thomas Hunt Morgan
(1966-1945)
Discovered the 3rd basic genetic law, together
with Mendels two laws, they form the basis of
what is now known as classical genetics.
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James Watson Francis Crick
Elucidation of the double helix structure of
DNA molecule is one of the most important
scientific discovery in the 20th century, which
symbols the birth of Molecular Genetics.
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Epigenetics ---- non-Mendelian genetics
Lamarckian phenomenon
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Before 1800, Lamarck was an essentialist who
believed species were unchanging however, after
working on the molluscs of the Paris Basin, he
grew convinced that transmutation or change in
the nature of a species occurred over time. He
set out to develop an explanation, which he
outlined in his 1809 work, Philosophie
Zoologique. Lamarck developed two laws to
explain evolution
The law of use and disuse In every animal which
has not passed the limit of its development, a
more frequent and continuous use of any organ
gradually strengthens, develops and enlarges that
organ, and gives it a power proportional to the
length of time it has been so used while the
permanent disuse of any organ imperceptibly
weakens and deteriorates it, and progressively
diminishes its functional capacity, until it
finally disappears.
The law of inheritance of acquired
characteristics All the acquisitions or losses
wrought by nature on individuals, through the
influence of the environment in which their race
has long been placed, and hence through the
influence of the predominant use or permanent
disuse of any organ all these are preserved by
reproduction to the new individuals which arise,
provided that the acquired modifications are
common to both sexes, or at least to the
individuals which produce the young. The idea of
passing on to offspring characteristics that were
acquired during an organism's lifetime is called
Lamarckian.
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Traditional examples considered as Lamarckian
inheritance
Giraffes stretching their necks to reach leaves
high in trees (especially Acacias), strengthen
and gradually lengthen their necks. These
giraffes have offspring with slightly longer
necks (also known as "soft inheritance").
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Traditional examples considered as Lamarckian
inheritance
A blacksmith, through his work, strengthens the
muscles in his arms. His sons will have similar
muscular development when they mature.
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Like many of his generation, Kammerer undertook
numerous experiments, largely involving
interfering with the breeding and development of
amphibians. He interested himself in the
Lamarckian doctrine of acquired characteristics
and eventually reported that a Midwife toad was
exhibiting a black pad on its foot - an acquired
characteristic brought about by adaptation to
environment. Claims arose that the result of the
experiment had been falsified. The most notable
of these claims was made by Dr. G. K. Noble,
Curator of Reptiles at the American Museum of
Natural History, in the scientific journal
Nature.1 He reported that the black pad
actually had a far more mundane explanation it
had simply been injected there with Indian ink.
Six weeks later, Kammerer committed suicide.
Paul Kammerer (1880-1926)
1971. , ISBN 0-394-71823-2. An account of Paul
Kammerer's research on Lamarckian evolution and
what he called "serial coincidences".
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Darwin wrote in 1861 Lamarck was the first man
whose conclusions on the subject excited much
attention. This justly celebrated naturalist
first published his views in 1801. . . he first
did the eminent service of arousing attention to
the probability of all changes in the organic, as
well as in the inorganic world, being the result
of law, and not of miraculous interposition.
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Science 7 April 2000Vol. 288. no. 5463, p. 38
Was Lamarck Just a Little Bit Right? Michael
Balter Although Jean-Baptiste Lamarck is
remembered mostly for the discredited theory that
acquired traits can be passed down to offspring,
new findings in the field of epigenetics, the
study of changes in genetic expression that are
not linked to alterations in DNA sequences, are
returning his name to the scientific literature.
Although these new findings do not support
Lamarck's overall concept, they raise the
possibility that "epimutations," as they are
called, could play a role in evolution.
Lamarck was a true pioneer of evolutionary
theory!
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Lecture I General Overview and History of
Epigenetics
Various aspects of the modern understanding of
epigenetic inheritance are reminiscent of
Lamarck's ideas about evolution.
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Lecture I General Overview and History of
Epigenetics
The Historic and modern definitions of
Epigenetics
The term 'epigenetics' was introduced by Conrad
H. Waddington in 1942 to describe the
interactions of genes with their environment that
bring the phenotype into being.
Conrad H. Waddington (1905-1975)
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Lecture I General Overview and History of
Epigenetics
The chromatin structure plays an important role
in regulation of gene expression, while the tail
modifications in the histones play an important
role in the chromatin structure.
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Lecture I General Overview and History of
Epigenetics
Epigenetic inheritance Epigenetic inheritance is
the transmission of information from a cell or
multicellular organism to its descendants without
that information being encoded in the nucleotide
sequence of the genes. Epigenetic inheritance
occurs in the development of multicellular
organisms dividing fibroblasts for instance give
rise to new fibroblasts even though their genome
is identical to that of all other cells.
Epigenetic transmission of traits also occurs
from one generation to the next in some
organisms, though it is comparatively rare. It
has first been observed in maize.
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Champion of Chromatin and Pioneer of Epigenetics
Alan Wolffe (1959-2001)
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Genetics
Epigenetics
alterations
mutations
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How are epigenetic variations accomplished?
Epigenetic effects can be accomplished by several
self-reinforcing and inter-related covalent
modifications on DNA and/or chromosomal proteins,
such as DNA methylation and histone
modifications, and by chromatin remodeling, such
as repositioning of nucleosomes. These heritable
modifications are collectively termed
epigenetic codes (reviewed in Richards and
Elgin, 2002).
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Three types of Epigenetic variations
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Four classical epigenetic phenomena

• Position-Effect Variegation (PEV) (H.J. Muller,
  1930)

• Paramutation (R.A. Brink, 1958)

• X-chromosome Inactivation (M.F. Lyon, 1961)

• Genomic Imprinting

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Paramutation (R.A. Brink, 1958)
Brink described his stunning observations of
paramutation at the R locus in maize in 1958.
Several similar loci were later again discovered
in maize.
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The mop1 (mediator of paramutation1) mutation
(A) B Mop1/mop1
(B) B mop1/mop1
(C) B-I Mop1/Mop1
(D) B mop1/mop1 with B-like sectors
(F) Pl mop1/mop1
(E) Pl Mop1/mop1
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Molecular mechanism of X chromosome inactivation
Chow et al. (2005) Annu. Rev. Genomics Hum.
Genet. 6 69-92.
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Human genes escaping from X inactivation
624 genes were tested in nine Xi hybrids. Each
gene is linearly displayed. Blue denotes
significant Xi gene expression, yellow shows
silenced genes, pseudoautosomal genes are purple,
and untested hybrids remain white. Positions of
the centromere (cen) and XIST are indicated.
Carrel and Willard, 2005, Nature 434 400-4.
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Genomic imprinting
Genomic imprinting is a genetic phenomenon by
which certain genes are expressed in a
parent-of-origin-specific manner. It is an
inheritance process independent of the classical
Mendelian inheritance. Imprinted genes are either
expressed only from the allele inherited from the
mother (eg. H19 or CDKN1C), or in other instances
from the allele inherited from the father (eg.
IGF2). Forms of genomic imprinting have been
demonstrated in insects, mammals and flowering
plants.
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Genomic imprinting can be defined as the
gamete-of-origin dependent modification of
phenotype.
Paternal imprinting means that an allele
inherited from the father is not expressed in
offspring. Maternal imprinting means that an
allele inherited from the mother is not
expressed in offspring.
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"parent-of-origin effects" discovered 3000 years
ago by mule breeders in Asia.
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Imprinted genes in plants
Decades after imprinting was demonstrated in the
mouse, a similar phenomena was observed in
flowering plants (angiosperms). During
fertilisation of the embryo in flowers, a second
separate fertilisation event gives rise to the
endosperm, an extraembryonic structure that
nourishes the seed similar to the mammalian
placenta. Unlike the embryo, the endosperm often
contains two copies of the maternal genome and
fusion with a male gamete results in a triploid
genome. This uneven ratio of maternal to paternal
genomes appears to be critical for seed
development. Some genes are found to be expressed
from both maternal genomes while others are
expressed exclusively from the lone paternal
copy.30
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What do we learn from the last four classical
epigenetic cases?
Controlled by non-coding RNA and DNA/histone
modification
Significant variability/stability (PEV, ina-X)
Reversible and/or transmittable through germ cells
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Imprinting mechanisms
Imprinting is a dynamic process. It must be
possible to erase and re-establish the imprint
through each generation. The nature of the
imprint must therefore be epigenetic
(modifications to the structure of the DNA rather
than the sequence). In germline cells the imprint
is erased, and then re-established according to
the sex of the individual i.e. in the developing
sperm, a paternal imprint is established, whereas
in developing oocytes, a maternal imprint is
established. This process of erasure and
reprogramming is necessary such that the current
imprinting status is relevant to the sex of the
individual. In both plants and mammals there are
two major mechanisms that are involved in
establishing the imprint these are DNA
methylation and histone modifications.
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Some other important epigenetic phenomena
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Bookmarking
In genetics and epigenetics, bookmarking is a
biological phenomenon believed to function as an
epigenetic mechanism for transmitting cellular
memory of the pattern of gene expression in a
cell, throughout mitosis, to its daughter cells.
This is vital for maintaining the phenotype in a
lineage of cells so that, for example, liver
cells divide into liver cells and not some other
cell type.
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Soft inheritance
Soft inheritance is the term coined by Ernst
Mayr to include such ideas as Lamarkism. It
contrasts with modern ideas of inheritance, which
Mayr called hard inheritance. Since Mendel,
modern genetics has held that the hereditary
material is impervious to environmental
influences (except, of course, mutagenic
effects).1 In soft inheritance "the genetic
basis of characters could be modified either by
direct induction by the environment, or by use
and disuse, or by an intrinsic failure of
constancy, and that this modified genotype was
then transmitted to the next generation."2
Concepts of soft inheritance are usually
associated with the ideas of Lamarck and
Geoffroy. Recent work in plants and mammals on
the role of the environment on epigenetic
modifications of DNA have led to the argument
that inherited epigenetic variation is a kind of
soft inheritance.1
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Most recently reported important epigenetic
phenomena
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Too big! Apparently as a result of abnormal
imprinting, the cloned lamb at left is bigger
than the normal lamb at right. Cloned animals
often have other health problems as well.
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• Epigenetic variation among monozygous twins

Monozygous twins are considered genetically
identical, but significant phenotypic discordance
between them exist, which is particularly
noticeable for psychiatric diseases.
Although MZ twins are epigenetically
indistinguishable during early years of life,
older MZ twins exhibited remarkable differences
in their overall content and genomic distribution
of 5-methylcytosine DNA and histone acetylation,
affecting their gene expression portrait.
Fraga et al. 2005, PNAS 102 10604-9
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• Trans-generational inheritance of epigenetic
  variation
• Consider an epigenetic mark (e.g. DNA
  methylation) that exists at a hypothetical locus
  in the primordial germ cells of the parent. Most
  aberrant epigenetic marks will be erased during
  the genome-wide epigenetic reprogramming during
  gametogenesis, and the mature gametes will not
  carry this mark. Occasionally, epigenetic marks
  escape reprogramming and are maintained in the
  mature gametes. These marks are transmitted to
  the offspring. There is a second wave of
  genome-wide epigenetic reprogramming around the
  time of blastocyst formation and some marks
  transmitted by the parent are erased at this
  stage. Marks that survive this reprogramming are
  then inherited by the offspring and have the
  potential to influence phenotypic outcomes.

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The agouti locus in mouse
Epigenetic regulation of the agouti gene in Avy/a
mice. Phaeomelanin (the product of the agouti
gene) is not produced from the a allele because
the agouti gene is mutated. Two potential
epigenetic states of the Avy allele can occur
within cells of Avy/a mice. The IAP that lies
upstream of the agouti gene can remain
unmethylated, allowing ectopic expression of the
gene from the IAP and resulting in a yellow coat
colour (top). Alternatively, the IAP can be
methylated, so that the gene is expressed under
its normal developmental controls, leading to a
brown coat colour. If the IAP methylation event
occurs later in development and does not affect
all embryonic cells, the offspring will have a
mottled appearance (illustrated on the right).
Right Genetically identical week 15 Avy/a mouse
littermates are shown, representing five
coat-colour phenotypes. Mice that are
predominately yellow are also clearly more obese
than the brown mice
Jirtle and Skinner 2007 Nat. Reviews Genetics 8
253-262
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Epigenetics and hybrid speciation
O'Neill RJ, O'Neill MJ, Graves JA.
1998. Undermethylation associated with
retroelement activation and chromosome
remodelling in an interspecific mammalian
hybrid.Nature 1998 393 68-72
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How widely exist about such environmentally
induced variation in the nature?
To what extent such variation contributed to
evolution?
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• Epigenetic Variation significance and
  implications

1. Phenotypic variation is traditionally parsed
into components that are directed by genetic and
environmental variation. Now the line between
these two components is blurred by inherited
epigenetic variation.
2. How widely exist about the inheritable
epigenetic variation in the nature? Could
inheritance of epigenetic variants be an
important means of adaptive evolution in the face
of environmental change, without a permanent
alteration in the DNA? Whats the difference
between inheritable epigenetic variation and
neo-Lamarckian?
3. There is an increasing belief that epigenetic
variants and inheritance could provide the
missing piece of the puzzle for understanding the
basis of many complex phenotypes.
4. Our understanding of epigenetic variation and
inheritance is still in its infancy, and it is
unclear what proportion of heritable phenotypic
variability can be ascribed to epigenetic factors.
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Epigenetics and chromatin state
Non-coding RNAs play a central role!
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Thank you for your attention in Lecture I !