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Epigenomics Scientific Background

Created: ; Last Update: January 20, 2011.

About Epigenetics

Summary

Gene expression profiles can remain stable for many cell generations, then become reprogrammed at precise points during development or in response to environmental factors. How does this work?

What is Epigenetics?

Interest in epigenetics has exploded in recent years, but the central question it aims to answer has been with us for decades: how do the many cell types of the body maintain drastically different gene expression patterns while sharing exactly the same DNA?

Epigenetics refers to a gene activity state that may be stable over long periods of time, persist through many cell divisions, or even be inherited through several generations, all without any change to the primary DNA sequence [Roloff and Nuber 2005, Ng and Gurdon 2008, Probst et al 2009].

How does this work?

One of the best understood molecular mechanisms behind epigenetics involves methylation of cytosine residues at specific positions in the DNA molecule [Bestor 2000, Bird 2002]. The enzymes that carry out the methylation reaction have been well characterized [Okano et al 1999], as is the mechanism by which the configuration of methylated positions is propagated through DNA replication [Groth et al 2007]. The typical consequence of methylation in a genomic region is the repression of nearby genes [Bird 2002]. (See also About DNA Methylation)

Another mechanism of epigenomic control is at the level of chromatin. In the cell, DNA is associated with histone proteins to form chromatin. Packaging of DNA into chromatin can render large regions of the DNA inaccessible and prevent processes such as DNA transcription from occurring. Histones proteins can be chemically modified (by acetylation, methylation, sumoylation, and ubiquitylation) which can cause structural changes in chromatin making the DNA accessible [Kouzarides 2007]. (See also About Chromatin Structure.)

Non protein coding RNAs (ncRNAs] also contribute to epigenetic regulation. ncRNA molecules can be processed and participate in RNA interference pathways. This process generates small RNA molecules that can inhibit gene expression by interactions with the nascent RNA molecule, DNA itself or participating in recruitment of chromatin modifiers [Mattick et al 2009, Zaratiegui et al 2007]. Additionally, other ncRNA molecules participate in long range silencing events where large chromosomal regions, even whole chromosomes, can become transcriptionally inactive [Clark 2007, Yang and Kuroda 2007]. (See Figure 1).

Figure 1. . Epigenetic mechanisms regulate chromatin structure.

Figure 1.

Epigenetic mechanisms regulate chromatin structure. DNA methylation and histone modifications both participate in modulating chromatin structure.

The Epigenome

These mechanisms of epigenetic regulation contribute to the epigenome. The distribution of methylated DNA, histone modifications, and ncRNA expression may not only be specific to a particular organism, but it will be specific to a particular tissue, or even one particular cell type. The epigenome is not static like the genome. The epigenome can be dynamic, influenced by environmental factors and extracellular stimuli, and change in response to these factors. Misregulation of these epigenetic events has been observed in various cancers and human diseases. Understanding how the epigenome contributes to gene regulation will give us greater insight into human disease.

Keyword: epigenetic mechanisms

About DNA Methylation

Summary

The first discovered epigenetic modification is methylation of cytosine residues in DNA molecules. DNA methylation, the first recognized and most well-characterized modification, is linked to transcriptional silencing and is important for gene regulation, development, and tumorigenesis [Feinberg and Tycko 2004, Esteller 2008, Jones and Baylin 2007]

The Enzymology of DNA Methylation

In mammalian cells, methylation of cytosine residues is catalyzed by DNA methyltransferases (DNMTs), including DNMT1, DNMT3a and DNMT3b [Chen and Li 2004, Bestor 2000]. DNMT3a and DNMT3b are involved in de novo methylation, which may occur in embryonic stem cells or cancer cells [Okano et al 1999]. DNMT1 maintains the genomic methylation state by specifically recognizing and methylating hemimethylated CpG dinucleotides during DNA replication [Groth et al 2007, Li et al 1992]. (See Figure 2).

Figure 2. . Mechanism for maintaining DNA methylation during replication.

Figure 2.

Mechanism for maintaining DNA methylation during replication. Following replication, individual strands of the original molecule become paired with newly synthesized strands (in green), resulting in a hemimethylated DNA. DNA methyltransferase 1 (DNMT1) (more...)

DNA Methylation and Disease

Aberrant patterns of DNA methylation influence many aspects of disease processes [Ozanne and Constância 2007, Feinberg and Tycko 2004, Jaenisch and Young 2008], particularly in many human tumors [Esteller 2008, Jones and Baylin 2007]. Cancers have the unique property in which global hypomethylation alters the chromatin architecture, leading to the inappropriate activation of oncogenes. In constrast, hypermethylation and silencing of tumor suppressor genes is recognized as a hallmark of many types of cancer cells [Feinberg and Tycko 2004, Laird 2003, Callinan and Feinberg 2006].

Keyword: DNA methylation

About Histone Modifications

Summary

Histone proteins undergo a bewildering array of post-translational modifications, which may be associated with active or inactive chromatin. The presence and phenotypic influence of these modifications contribute to the epigenome of the cell.

The Role of Histone Modifications

Histone modifications are diverse, and typically evolutionarily conserved. Modifications that have been observed include lysine and arginine methylation, lysine acetylation, serine and threonine phosphorylation, monoubiquitylation, sumoylation and proline isomerization [Kouzarides 2007]. Histone modifications are dynamic, and their deposition or removal can be influenced by factors including developmental state, environmental cues, exposure to stress, and the cell cycle. Various modifications are associated exclusively with actively transcribed regions of the genome, while other modifications have been observed to localize to regions of inactive chromatin [Kouzarides 2007]. For example, methylation on histone H3 at lysine 4, lysine 36 and lysine 79 are marks that localize to regions of the genome that are transcriptionally active, while methylation on histone H3 lysine 9, lysine 27 and histone H4 lysine 20 are marks that localize to regions of the genome that are transcriptionally inactive [Martin and Zhang 2005, Kouzarides 2007].

How many of these modifications exert their biological effects, and how the addition or removal of many of these modifications is regulated is still unclear. In many cases, recognition of specific histone modifications by various effector proteins is thought to mediate specific biological processes such as gene activation or gene repression [Taverna et al 2007]. Additionally, alteration of histone charges by modifications such as acetylation and phosphorylation are thought to induce localized structural changes in chromatin allowing protein factors to access the DNA. The dependence of certain histone modifications on other modifications, and antagonism of some histone marks by others has been observed. The combinatorial nature of various histone modifications occurring at different times during development and at specific sites within the histones provides additional levels of regulation and complexity to the epigenome. Misregulation of the addition and/or removal of these modifications, or the enzymes that catalyze them have been implicated in human disease, including various cancers [Schneider et al 2002].


Keyword: histone modification

About notation of histone modifications

Summary

A wide array of histone modifications has been identified and a standardized nomenclature has been devised for presenting them.

The Brno nomenclature was created by a consortium of European laboratories to standardize notation for histones and histone modifications [Turner 2005]. An example of this notation is shown in Figure 1, the histone protein (H3, H4, H2A, or H2B) is indicated first, followed by the amino acid that is modified (i.e. “K27” representing lysine 27). This is followed by the type of modification that is observed (i.e. “me3” represents tri-methylation). (See Figure 3)

Figure 3. . Brno notation of histone modifications.

Figure 3.

Brno notation of histone modifications.

Histone proteins can be extensively modified with a wide array of posttranslational modifications. These modifications include lysine and arginine methylation, lysine acetylation, serine and threonine phosphorylation, monoubiquitylation, sumoylation and proline isomerization [Kouzarides 2007]. Table 1 lists various types of modifications that have been identified.

Table 1.

Amino acidModificationAbbreviation
Lysinemono-methylationme1
di-methylationme2
tri-methylationme3
acetylationac
mono-ubiquitylationub
poly-ubiquitylationubn
 sumoylationsu
Argininemono-methylationme1
di-methylation (symmetrical)me2s
di-methylation (asymmetrical)me2a
Serinephosphorylationph
Threoninephosphorylationph
GlutamateADP-ribosylationar

Various modifications have been associated with actively transcribed regions of the genome, while other modifications have been observed to localize to regions of inactive chromatin [Kouzarides 2007]. Understanding how these effects are mediated are currently of great interest. Table 2 lists specific histone modifications that have been identified experimentally and indicates their proposed biological functions within the cell.

Table 2:

Histone modifications and their proposed biological functions

HistoneAmino acidModificationBiological role
H3R2me2agene activation
T3phmitosis
K4acgene activation
K4me1, me2, me3gene activation
R8me2sgene repression
K9acgene activation
K9me1, me2, me3gene repression
S10phmitosis
S11phmitosis
K14acgene activation
R17me2agene activation
K18acgene activation
K23acgene activation
R26me2agene activation
K27acgene activation
K27me1, me2, me3gene repression
S28phmitosis
K36me1, me2, me3gene activation
K56acgene activation
K79me1, me2, me3gene activation
H4S1phmitosis
R3me2agene activation
R3me2sgene repression
K5acgene activation
K8acgene activation
K12acgene activation
K16acgene activation
K20me1, me2, me3gene repression
K91acgene activation
H2AS1phmitosis
K4¥acgene activation
K5acgene activation
K7¥acgene activation
T119*phmitosis
K126¥sugene repression
K119ubgene activation
S129¥phDNA repair
H2BK5acgene activation
S10¥phapoptosis
K12acgene activation
S14phapoptosis
K15acgene activation
K16¥acgene activation
K20acgene activation
S33*phgene activation
K120ubmeiosis
K123¥ubgene activation
¥

S. cerevisiae , *D. melanogaster

Table 2 adapted from: Allis, C.D., Jenuwein, T., Reinberg, D. (2007). Epigenetics. Plainview, NY. Cold Spring Harbor Laboratory Press.

About Chromatin Structure

Summary

Changes in chromatin conformation affect the accessibility of genes to transcription factors.

The Nucleosome: The Building Block of Chromatin

In the nucleus of a cell DNA is wrapped around two copies of each of the four core histone proteins H3, H4, H2B, and H2A to form the nucleosome which is the fundamental repeating unit of chromatin.These nucleosomes are condensed into higher order structures which form chromatin . This is necessary for efficient packaging of the DNA into the nucleus of the cell. When the DNA is compacted into this structure, its accessibility becomes greatly limited, and this serves as a mechanism by which the cell regulates DNA mediated processes such as transcription, DNA replication, and DNA repair [Kouzarides 2007, Vaquero et al 2003].

Each histone is composed of a conserved globular histone-fold domain, and extended N and C-terminal tails. The globular domains of the histone proteins form the nucleosome core, which 146 base pairs of DNA are wrapped around. The extended histone tails protrude beyond the DNA and into the nucleoplasm. These tails serve as the sites of a variety of post-translational modifications, such as acetylation, methylation, ubiquitylation and phosphorylation [Vaquero et al 2003]. These modifications have been observed to influence chromatin structure. The presence or absence of certain post-translational modifications can allow localized decondensation or condensation of the chromatin fiber. These localized changes in chromatin structure can exert a positive or negative regulatory effect on DNA-mediated processes such as gene regulation, DNA repair and DNA replication [Kouzarides 2007, Vaquero et al 2003]. The contribution of these modifications to the regulation of these processes is one aspect of the field of epigenetics.

Several aspects of chromatin structure, such as accessibility to factors and precise nucleosome positioning and occupancy influence gene expression. Typically, regions of the genome that are transcriptionally active or are functioning in a regulatory capacity (e.g., promoters, enhancers, insulators) remain in an ‘open’ or accessible state. This can be influenced in trans, by DNA binding proteins that possess chromatin remodeling activities and the epigenetic mechanisms described above and in cis by nucleosome position and occupancy influenced by DNA sequences. These open regions of the genome can be assayed by nuclease sensitivity, and this has been employed extensively to identify regulatory sequences occurring within the cellular genome [Gross and Garrard 1988]. (See Figure 4).

Figure 4.

Figure 4.

The building block of chromatin, the nucleosome is composed of an octamer of histone proteins which is wrapped by 146 base pairs of DNA

Keyword: histone modification

About small RNAs

Summary

Small non-coding RNAs have an important role in regulating gene expression.

Non-Coding RNA and The Epigenome

Three major classes of small non-coding RNAs have been shown to play a critical role in regulating gene expression in both plant and animal systems. The processes directed by these small RNAs confer resistance to a variety of cellular insults, such as viral infection and preventing random transposition events within the genome. Additionally, small RNAs have been shown to be important for directing other epigenetic processes, such as DNA methylation and chromatin modification [Mattick et al 2009, Carthew and Sontheimer 2009, Ghildiyal and Zamore 2009].

Small interfering RNA (siRNA)

In 2006 Craig Mello and Andrew Fire were awarded the Nobel Prize in Physiology or Medicine for the discovery of RNA interference. It had previously been known that normal gene expression could be interrupted by the introduction of anti-sense RNA into the cell [Izant and Weintraub 1984]. Using the worm C. elegans as a model system they observed that this process was greatly enhanced by using double stranded RNA molecules (dsRNA) [Fire et al 1998]. It was later observed that these long dsRNAs can be processed into short 21-24 nucleotide fragments. These processed RNA fragments were identified as precursors to short interfering RNAs (siRNAs) and shown to play a role in regulating gene expression post-transcriptionally [Elbashir et al 2001]. siRNAs can be derived from both exogenous sources (such as viral infection) or endogenous sources of dsRNA (such as convergent or bidirectional transcription of transposons and repetitive elements) [Ghildiyal and Zamore 2009].

Micro RNA (miRNA)

Micro RNAs (miRNAs) are another class of small RNAs that play a role in gene regulation. Unlike many siRNA molecules, miRNAs are derived from endogenous sources [Tomari and Zamore 2005]. Hundreds of miRNA genes have already been identified in the human genome. Many times these miRNA genes occur in clustered loci . miRNA genes are transcribed by RNA polymerase II and the resulting transcript is called the primary miRNA (pri-miRNA) [Carthew and Sontheimer 2009, Ghildiyal and Zamore 2009]. The pri-miRNA is processed into a 60-70 base pair RNA fragment that forms a structured hairpin known as the pre-miRNA [Bartel 2004]. Similar to siRNA processing, pre-miRNAs are also processed by Dicer into short double stranded RNA molecules. In this case one of the strands is designated the miRNA strand and the other the miRNA* strand. This miRNA-miRNA* duplex associates with Argonaute family protein members, the miRNA* strand is degraded and the miRNA is directed to its target. The degree of complementarity between the miRNA and the target mRNA can dictate whether the target mRNA is degraded or translationally blocked. Strong pairing with the mRNA target stimulates cleavage by endonuclease, while weaker pairing can interfere with translation and direct degradation of mRNA. Varying complementarity means that a particular miRNA has the potential to affect multiple targets [Carthew and Sontheimer 2009, Ghildiyal and Zamore 2009]. Currently, it is known that miRNAs can behave as oncogenes and tumor suppressor genes. It has been observed that certain miRNAs are upregulated in certain tumor types, and others play critical roles in cell cycle progression [Negrini et al 2009].

Piwi-interacting RNA (piRNA)

A third class of small RNAs is called piRNAs. Unlike miRNAs and siRNAs. piRNAs do not interact with and are not processed by the protein Dicer. piRNAs are derives from long single stranded RNA molecules and interact with a sub-family of the Argonaute proteins, called Piwi proteins. The piRNA precursor is then processed into a shorter 26-31 nucleotide piRNA. piRNAs have been shown to play a critical role in silencing transposons in germ-line cells. Currently piRNA generation and mechanism of action are not well understood [Carthew and Sontheimer 2009, Ghildiyal and Zamore 2009].

About Chromatin Modifying Enzymes

Summary

A diverse family of proteins catalyzes the addition of functional groups to histone proteins. These modifications can participate in modulating chromatin structure and function. There are two principle ways this is thought to be accomplished. First, modifications can affect chromatin structure directly by altering the charges of histone proteins and causing localizes relaxation of chromatin structure. Secondly, these modifications can act indirectly, by serving as recognition and binding sites for various classes of effector proteins that may participate in chromatin remodeling.

Histone modification “writers”

There is a wide array of known histone modifications, including acetylation, methylation, phosphorylation, ubiquitylation, and SUMOylation. Likewise, these modifications are added to and/or removed from histone proteins by diverse families of proteins including histone acetyltransferases/deacetylases, histone methyltransferases/demethylases, histone kinases/phosphatases, and ubiquitin ligases.

Histone Acetylation

Histone acetylation is a dynamic process, and the acetyl state of particular lysine can be rapidly changed. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are the enzymes that are responsible for the addition and removal of this modification, and target particular lysine residues. These proteins are typically part of larger protein complexes, which contain various other factors important for recruitment or for coactivation/corepression. One of the more heavily studied HDACs, Sir2, a NAD dependant histone deacetylase, has been shown to be important for the maintenance of silent chromatin and has been implicated as a major regulator of cell aging [Vaquero 2007]. Currently, HDAC inhibitor compounds are being explored and utilized as anti-cancer therapies.

Histone Methylation

One of the most well characterized histone modifications is histone methylation. Histones can be methylated on both lysine and arginine residues, and these marks have also shown to be evolutionarily conserved. Unlike histone acetylation, histone methylation does not affect the charge of the modified amino acid. In addition, each lysine is able to accept up to three methyl groups, resulting in mono-, di-, and trimethylated lysine forms [Martin 2005]. In many cases, each of these methyl-lysine forms are detectable in the cell at any given time, and have distinct localization patterns, suggesting that each modified form of lysine has a distinct biological role [Zhang 2001, Vaquero 2003, Martin 2005]. Unlike histone acetylation, in which the presence or absence of the modification contributes to an epigenetic state, the location of the methyl mark on the histone dictates its function. For example, methylation on histone H3 at lysine 4, lysine 36 and lysine 79 are marks that localize to regions of the genome that are transcriptionally active, while methylation on histone H3 lysine 9, lysine 27 and histone H4 lysine 20 are marks that localize to regions of the genome that are transcriptionally inactive [Martin 2005, Kouzarides 2007].

The main family of enzymes that catalyze histone lysine methylation contain the conserved SET domain. This domain, named for the proteins it was first discovered in (Su(var)3-9, Enhancer of zeste, and Trithorax), is evolutionarily conserved and found in organisms ranging from fungi to humans. In mammals and higher eukaryotes, multiple SET domain containing proteins can methylate a particular lysine [Zhang 2001]. Misregulation of these proteins, through overexpression, deletion or chromosomal translocations has been implicated in many types of human cancers. For example, misregulation of MLL1, a human H3 lysine 4 methyltransferase has been implicated in myeloid/lymphoid or mixed lineage leukemia [Schneider 2002].

Histone Ubiquitination

Ubiquitin is a protein moiety, which is covalently attached to a protein through a series of enzymatic steps [Hochstrasser 1996, Hershko and Ciechanover 1998]. Polyubiquitination, or the addition of multiple ubiquitin moieties, is typically a signal for protein degradation that is mediated by the proteosome [Hochstrasser 1996, Hershko and Ciechanover 1998]. Monoubiquitination, or the addition of only a single ubiquitin has been observed on histones H2A and H2B has been observed and is thought to play a role in signaling [Goldknopf et al 1975, Osley 2004, Osley 2006, Weake and Workman 2008].

One mechanism by which monoubiquitylation of histones is thought to exert its effects is by serving as “wedge” which can open up or disrupt chromatin structure [Henry and Berger 2002]. Additionally, ubiquitinated histones might be recognized by various effector proteins to carry out downstream regulatory events [Weake and Workman 2008]. Ubiquitylation of histones has also been shown to be important for other histone modification events to occur. For example, it has been observed that ubiquitylation of histone H2B is necessary for di- and trimethylation of histone H3 at lysine 4 and lysine 79, demonstrating the complex and combinatorial nature of histone mofications [Briggs et al 2002, Sun and Allis 2002]. Furthermore, ubiquitylation of histones is reversible, as ubiquitin proteases have been identified that can remove this modification [Weake and Workman 2008].

The mechanism by which histone ubiquitylation contributes to epigenetic regulation is still unclear. It is interesting to note that monoubiquitylation on histone H2A has been demonstrated to play a role in transcriptional repression, while monoubiquitylation of histone H2B is implicated in transcriptional activation [Weake and Workman 2008].

Histone Phosphorylation

Phosphorylation of proteins usually occurs as part of a signaling pathway (e.g. MAP kinase pathways), and is a mechanism by which extracellular stimuli are “sensed” by the cell. Phosphorylation can serve as an activating signal on a target protein, such as a transcription factor, to stimulate a response to the external signal resulting in the up- or downregulation of specific genes [Turjanski et al 2007]. It is also thought that by histone phosphorylation, these signals can be directly transmitted to chromatin [Pokholok et al 2006].

Phosphorylation of histone proteins is another post-translational modification that has been observed [Kouzarides 2007, Cerutti and Casas-Mollano 2009]. Phosphorylation on histone H3 at serine 10 and serine 28 are both thought to be important for regulating chromatin condensation during mitosis [Garcia et al 2005, Bonenfant et al 2007]. The mechanism by which this occurs is unclear, but as with other modifications, it is thought that these modifications serve as sites of recognition for other factors and effector proteins, such as 14-3-3 proteins which can recognize phosphoserine residues and have been shown to interact with histone H3 [Macdonald et al 2005, Taverna 2007]. Additionally, phosphorylation of histone proteins may alter chromatin structure by affecting the charge of the histone proteins [Johansen and Johansen 2006].

“Reading” the histone marks

Experimental evidence suggests that the recognition of the methyl mark by various effector proteins is what determines whether the mark functions as an “active” mark or “inactive” mark [Taverna 2007]. Many proteins have domains that specifically recognize particular modifications. Several protein domains and their binding specificities have been characterized. PHD, or plant homeodomains have been shown to recognize methylated lysine residues. It is also interesting to note that the domains can recognize specific methyl forms, allowing for discriminate binding. Many of these PHD domain containing proteins have other enzymatic activities including nucleosome remodeling activity. For example, the protein factor BPTF contains a PHD finger that recognizes di- and tri-methylated H3K4. BPTF is a component of a chromatin an ATP dependent chromatin remodeling complex (NURF). Many other domains have been identified that can recognize methyl-lysine resides including chromodomains, MBT domains and WD40 repeats [Taverna 2007].

Bromodomains are another characterized protein domain that has been shown to recognize acetylated lysine residues. Many chromatin remodeling complexes contain proteins that contain bromodomains. For example that bromodomain in the histone acetyltransferase Gcn5 has been shown to recognize H4K16 acetlyation. It is thought that this recognition of H4K16ac by Gcn5 allows for the perpetuation of lysine acetylation to other lysine residues within the histone tail [Kuo et al 1996, Taverna 2007]. These are just two examples of how the histone marks deposited on chromatin are “read.”

Not only do histone modifications recruit enzymes that participate directly in chromatin remodeling activities, but dependence of certain histone modifications on other modifications, as well as antagonism of some histone marks by others has been observed. For example, it is known that ubiquitination on histone H2B is required for histone H3 lysine 4 and lysine 79 di- and trimethylation, thereby adding an additional level of regulation to these modifications [Briggs et al 2002, Sun and Allis 2002]. There is other evidence of similar events as well. For example, methylation occurs on histone H3 at lysine 9 while phopshorylation occurs on histone H3 at serine 10. During mitosis, phosphorylation occurs on H3 serine 10, and is thought to displace a protein important for chromatin silencing which is bound to methylated H3 lysine 9 [Cerutti and Casas-Mollano 2009]. Additionally, it is suggested that there are other factors in the cell that recognize histone H3 that is both methylated at lysine 9 and phosphorylated at serine 10, which may carry out a distinct functional role [Cerutti and Casas-Mollano 2009].

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