Transcript Lecture I

Course Title:
Epigenetics
Principle Lecturer:
Professor Bao Liu （刘宝）
E-mail: [email protected]
Homepage:
http://www.nenu.edu.cn/professor/pro/show.php?id=138
Other Lecturers:
Dr. Ningning Wang（王宁宁）
Dr. Jinsong Pang （庞劲松）
Dr. Yu Zhang (张瑜）
Key Laboratory of Molecular Epigenetics of MOE,
Northeast Normal University, Changchun, 130024, China
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
Lecture 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
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
Lecture 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
Father of Genetics,
discovered the basic laws of
heredity.
Gregor Mendel (1822-1884)
Thomas Hunt Morgan
(1966-1945)
Discovered the 3rd basic genetic law, together
with Mendel’s two laws, they form the basis
of what is now known as classical genetics.
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.
Mendelian
Genetics
Change in nucleotide
sequence
Alteration in gene
expression and/or function
Novel phenotype
Epigenetics ---- non-Mendelian genetics
Lamarckian phenomenon
Charles Darwin
(1809-1882)
Jean-Baptiste Lamarck
(1744-1829)
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.
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").
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.
Paul Kammerer
(1880-1926)
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.
1971. , ISBN 0-394-71823-2. An account of Paul Kammerer's research on Lamarckian
evolution and what he called "serial coincidences".
“Some authors use the term “variation” in
a technical sense, as implying a
modification directly due to the physical
conditions of life; and “variations” in this sense are
supposed not to be inherited; but who can say that
the dwarfed condition of shells in the brackish
waters of the Baltic, or dwarfed plants on Alpine
summits, or the thicker fur of an animal from far
northwards, would not in some cases be inherited
for at least a few generations?” (Darwin, 1859)
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.
Science 7 April 2000:Vol. 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!
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.
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)
The current concept of
epigenetics:
Changes in phenotype that are inheritable but do
not involve DNA mutation.
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.
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.
Champion of Chromatin and Pioneer of Epigenetics:
Alan Wolffe (1959-2001)
Genetics
Epigenetics
alterations
mutations
Changes in gene expression and/or function
and new phenotypes
How are epigenetic variations accomplished？
Epigenetic effects can be accomplished by several selfreinforcing 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).
Non-coding RNAs (samll RNAs)
Three types of
Epigenetic
variations:
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
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.
~9000 colorless seeds (B’/B-I) planted
B' plants (light pigmented plant, colorless kernels)
were crossed with B-Peru plants (nearly green
plant, purple kernels). The resulting seeds (B'/BPeru; purple kernels) gave rise to B' colored F1
plants. The F1 plants were crossed to B-I plants
(dark pigmented plant, colorless kernels), giving
rise to an ear segregating colorless (B'/B-I) and
purple (B-Peru/B-I) kernels. When the colorless
seeds were planted, the vast majority of the
resulting plants showed a B' plant phenotype
(B'/B-I' plants; the paramutation of B-I in these
plants is indicated as B'*). Two dark individuals
were isolated in which the B-I allele was not
paramutated. The B' allele in these individuals is
neutral for paramutation (B'-n).
Stam et al. (2002) Genetics
~6500 B’/B’* plants
2 B’-n/B-I plants
(100% paramutation) (No paramutation)
The mop1 (mediator of paramutation1) mutation
The mop1 mutations reactivate silenced
Mutator elements. Plants carrying
mutations in the mop1 gene also
stochastically exhibit pleiotropic
developmental phenotypes. Mop1 is an
RNA-dependent RNA polymerase gene
(RDRP), most similar to the RDRP in
plants that is associated with the
production of short interfering RNA
(siRNA) targeting chromatin. It was
proposed the mop1 RDRP is required to
maintain a threshold level of repeat
RNA, which functions in trans to
establish and maintain the heritable
chromatin states associated with
paramutation.
(A) B’ Mop1/mop1
(B) B’ mop1/mop1
(C) B-I Mop1/Mop1
(D) B’ mop1/mop1 with B’-like sectors
(E) Pl’ Mop1/mop1
(F) Pl’ mop1/mop1
Alleman et al. (2006) Nature
Molecular mechanism of X chromosome inactivation
Chow et al. (2005) Annu. Rev. Genomics Hum. Genet. 6: 69-92.
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.
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.
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.
Body color
(hypothetical)
"parent-of-origin effects" discovered ~3000 years ago
by mule breeders in Asia.
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]
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
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.
Some other important epigenetic
phenomena
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.
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]
Most recently reported important
epigenetic phenomena
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.
• 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
•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.
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
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
S
L
PL
How widely exist about such environmentally induced variation in the nature?
To what extent such variation contributed to evolution?
• 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? What’s 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.
Epigenetics and chromatin state
Non-coding RNAs play a central role!
Thank you for your attention in
Lecture I !