10.4Epigenetic Regulation of Gene Expression


Heterochromatin and Euchromatin

When the nucleus is stained with an alkaline staining agent and observed under a microscope, one can visualize strongly and weakly colored heterochromatin and euchromatin, respectively. In heterochromatin, yet another protein acts on the chromatin fibers to tightly condense the chromatin. This region accumulates unexpressed genes. Euchromatin is a loose collection of chromatin that accumulates genes that can be expressed.
Heterochromatin is believed to be either constitutive or facultative. Constitutive heterochromatin is formed throughout the life of the cell, and expression of genes contained within it is suppressed. One of the two X chromosomes found in females forms this type of constitutive heterochromatin. As a frequently mentioned example, the serum albumin gene is not expressed in cells found outside the liver and forms constitutive heterochromatin. Facultative heterochromatin changes the gene expression status by going back and forth between euchromatin and heterochromatin.

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Chromatin Structure and Gene Expression Regulation

Fig. 10-8 Schematic diagram of the epigenetic control mechanism

The nucleobase cytosine (C) is hypermethylated in DNA of constitutively repressed genes. In particular, 70% or more of cytosine residues in sequences with the two bases 5′-CG-3′ are methylated. When DNA constituting a nucleosome has a great deal of methylated cytosine, a protein complex recognizing this methylated cytosine binds it, and a histone-methylating enzyme contained in the complex methylates the histones. Then, another protein that associates with the methylated histones binds to that part of the chromatin and maintains it in a tightly condensed state (Fig. 10-8). This is called constitutive heterochromatin. In contrast, portions of DNA containing expressed genes are hypomethylated.

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What Is Epigenetic Regulation?

When a cell replicates, cytosine in the newly created DNA strands (the daughter strands) is not methylated. However, wherever the template strand (the parent strand) is methylated (the sequence on both strands is 5′-CG-3′), an enzyme methylates the cytosine in the corresponding portion of the daughter strand, and eventually, cytosines in the parent and daughter strands are methylated. Thus, during replication, the status of gene unexpressed and present as heterochromatin can be transmitted to the progeny cells. This resembles that any change in the DNA sequence (genetic changes are called “mutations”) would be transmitted to the progeny cell. However, because no changes occur in the base sequence, this process is called epigenetics*5. This type of gene expression regulation is referred to as epigenetic regulation (Fig. 10-8).

*5 The prefix “epi” means “over,” “above,” or “outer.”


DNA Methylation and Development and Cloning of Animals from Somatic Cells

DNA methylation is closely associated with heterochromatin formation, and genes in highly methylated parts of DNA are not expressed. DNA in the cells between the germ cell and early developmental stages is hypomethylated, i.e., all genes during this period can be expressed. In other words, such cells have totipotency, the ability to differentiate into any type of cell. As somatic cells become more differentiated during the developmental process, DNA methylation gradually proceeds, thus limiting the types into which the cells can differentiate, although the regions methylated differ by cell type. Subsequently, most genes associated with differentiation functions, except for some specific genes, become hypermethylated, indicating that they will never need to be expressed. Thus, although the mechanism of particular DNA regions becoming methylated during the developmental process is not yet clear, it can be understood that the developmental process is the process in which DNA methylation proceeds. One of the reasons for the low success rate of animal cloning from somatic cells is considered to be the lack of methods to efficiently transform hypermethylated DNA to a hypomethylated state (i.e., initialization).

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Histone Code

Histone methylation is an important modification, but it really is an oversimplification to state that its only function is to inhibit gene expression. This process is involved in inhibiting and promoting expression. For example, methylation of lysine 27 of histone H3 is observed in portions of unexpressed genes found in parts of heterochromatin, while methylation of lysine 4 of histone H3 is often observed in portions of expressed genes. Moreover, histone is subjected not only to methylation but also to acetylation and several other types of modifications (Fig. 10-9). Specific modifications of particular amino acids of histones function as “codes” involved in epigenetic regulation of gene expression, which is referred to as the “histone code.” Modifications of DNA bases as well as histones are involved in the mechanism supporting epigenetic inhibition.(see Selection 7 of Chapter 12)

Fig. 10-9 Histone code

K: lysine R: arginine S: serine
Red dot: methylated
Black dot: acetylated
White dot black circle: phosphorylated
Red U: ubiquitination*5

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Conveying Genetic Information

Genetic inheritance was originally understood to be a phenomenon in which a multicellular organism transfers its traits from the parent to the child, and the same phenomenon was also considered when a unicellular organism such as E. coli or paramecium transfers its traits to a progeny cell. Later, it was found that all organisms (prokaryotes or eukaryotes or unicellular or multicellular organisms) possess a common mechanism where DNA is the material that conveys traits, genetic information is carried by the DNA base sequence, and genes are located on specific regions.
In case of multicellular eukaryotic animals, which are composed of many different types of differentiated cells, almost all somatic cells constituting an individual are believed to have the same genetic composition. However, hepatic cells can only form new hepatic cells when they replicate and never form nerve or skin cells. As in this case, the phenomenon of a particular somatic cell passing on its particular traits to progeny somatic cells can be understood as the inheritance of traits from one cell to another. However, the base sequence of DNA (the genetic code) is identical in all somatic cells of the same individual in this case. Therefore, when particular traits belonging to a differentiated cell are passed to the progeny, a mechanism for controlling epigenetic gene expression, i.e., base modification through methylation and modification of histones (histone code), plays a vital role.
DNA is an important substance responsible for inheritance. However, recently from this background, the idea is emerging that histones should also be included as a substance responsible for inheritance and that genetic information is not only the DNA base sequence but also information on base modifications and the histone code.

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