Draft:Original research/Epigenomes

Inside each eukaryote nucleus is genetic material (DNA) surrounded by protective and regulatory proteins. These protective and regulatory proteins and the dynamic changes to them that occur during the course of a eukaryote's existence are the epigenome.

An epigenome consists of a record of the chemical changes to the DNA and histone proteins of an organism that can be passed down to an organism's offspring via transgenerational epigenetic inheritance, where changes to the epigenome can result in changes to the structure of chromatin and changes to the function of the genome.

Unlike the underlying genome which is largely static within an individual, the epigenome can be dynamically altered by environmental conditions.

Evolution
Evolution, the accumulation of change, while broadly applicable to anything which accumulates changes, is often thought of as gradual change or a series of changes, such as changes in the genetic composition of a population over successive generations.

Lamarckism
Lamarckism (or Lamarckian inheritance) is the idea that an organism can pass on characteristics that it acquired during its lifetime to its offspring (also known as heritability of acquired characteristics or soft inheritance). It is named after the French biologist Jean-Baptiste Lamarck (1744–1829), who incorporated the action of soft inheritance into his evolutionary theories.

After Erasmus Darwin wrote Zoonomia suggesting "that all warm-blooded animals have arisen ... with the power of acquiring new parts" in response to stimuli, with each round of "improvements" being inherited by successive generations", Jean-Baptiste Lamarck repeated in his Philosophie Zoologique of 1809 the folk wisdom that characteristics which were "needed" were acquired (or diminished) during the lifetime of an organism then passed on to the offspring.

Neo-Lamarckism is a theory of inheritance based on a modification and extension of Lamarckism, essentially maintaining the principle that genetic changes can be influenced and directed by environmental factors.

Epigenetics
Epigenetics is the study of genome or epigenome changes resulting from external rather than genetic influences.

"Epigenetic mechanisms are affected by several factors and processes including development in utero and in childhood, environmental chemicals, drugs and pharmaceuticals, aging, and diet. DNA methylation is what occurs when methyl groups, an epigenetic factor found in some dietary sources, can tag DNA and activate or repress genes. Histones are proteins around which DNA can wind for compaction and gene regulation. Histone modification occurs when 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. All of these factors and processes can have an effect on people's health and influence their health possibly resulting in cancer, autoimmune disease, mental disorders, or diabetes among other illnesses."

Epigenomic theory
Def. a chemical entity anterior to, after, at, besides, near to, on, outer to, over, related to, or upon another chemical is called an epi (or epi-) chemical.

Def. the "complete genetic information ... of an organism" is called a genome.

Here's a theoretical definition:

Def. a chemical entity anterior to, after, at, besides, near to, on, outer to, over, related to, or upon the complete genetic information of an organism is called an epi (or epi-) genome, or epigenome.

Genomes
The genome is the entirety of an organism's hereditary information. In humans, it is encoded in DNA. The genome includes both the genes and the non-coding sequences of the DNA.

Homo sapiens estimated genome size [is] 3.2 billion bp.

Genetic information is encoded as a sequence of nucleobases: adenine (A), cytosine (C), guanine (G), and thymine (T).

Deoxyribonucleic acid molecules
Deoxyribonucleic acid (DNA) is composed of nucleobases (the sequence of which is the genome), deoxyribose (a sugar), and phosphate groups. Each nucleobase is attached to one deoxyribose molecule and one (PO4) phosphate molecule to form a chain of nucleotides (nucleobase + deoxyribose + phosphate) for a haploid genome. A linking of nucleobases may occur without the phosphate or the deoxyribose. The phosphate and the sugar are part of the epigenome.

DNA often occurs as a double helix. The linking between one nitrogenous nucleobase of a DNA molecule and another nitrogenous nucleobase of a second DNA molecule is via hydrogen bonds. Each hydrogen bond (the electromagnetic attractive interaction of a hydrogen atom and an electronegative atom, such as nitrogen or oxygen of a nucleobase) is part of the epigenome.

The structure a DNA molecule shown in the top image on the left depends on its environment. In aqueous environments, including the majority of DNA in a cell, B-DNA is the most common structure. The A-DNA structure dominates in dehydrated samples and is similar to the double-stranded RNA and DNA/RNA hybrids. Z-DNA is a rarer structure found in DNA bound to certain proteins.

Nucleosomes
DNA packaging in eukaryotes consists of "DNA wound in sequence around four histone protein cores.

Nucleosomes form the fundamental repeating units of eukaryotic chromatin.

The nucleosome core particle consists of approximately 147 base pairs of DNA wrapped in 1.67 left-handed superhelical turns around a histone octamer consisting of 2 copies each of the core histones H2A, H2B, H3, and H4.

Core particles are connected by stretches of "linker DNA", which can be up to about 80 bp long.

Histones
Histone deacetylases (HDAC) ([Enzyme Commission number] EC number 3.5.1) are a class of enzymes that remove acetyl groups (O=C-CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly.

Histone deacetylase action is opposite to that of histone acetyltransferase.

Chromatin
Chromatin, or the Chromatin network, is a complex of macromolecules found in cells, consisting of DNA, protein, and RNA.

DNA which codes genes that are actively transcribed ("turned on") is more loosely packaged and associated with RNA polymerases (referred to as euchromatin) while that DNA which codes inactive genes ("turned off") is more condensed and associated with structural proteins (heterochromatin).

Polycomb-group proteins play a role in regulating genes through modulation of chromatin structure.

Euchromatin
Def. "uncoiled dispersed threads of chromosomal material that occurs during interphase" is called euchromatin.

The structure of euchromatin is reminiscent of an unfolded set of beads along a string, wherein those beads represent nucleosomes.

The presence of methylated lysine 4 on the histone tails may act as a general marker for euchromatin.

One example of constitutive euchromatin that is 'always turned on' is housekeeping genes, which code for the proteins needed for basic functions of cell survival.

Heterochromatin
Heterochromatin mainly consists of genetically inactive satellite sequences, and many genes are repressed to various extents, although some cannot be expressed in euchromatin at all. Both centromeres and telomeres are heterochromatic, as is the Barr body of the second, inactivated X-chromosome in a female.

Constitutive heterochromatin
Sections of DNA that occur particularly at the centromeres and telomeres often consisting of repetitive DNA that is largely transcriptionally silent are constitutive heterochromatin.

Regions of DNA that exist as constitutive heterochromatin are the same for all cells of a given species.

All human chromosomes 1, 9, 16, and the Y-chromosome contain large regions of constitutive heterochromatin. In most organisms, constitutive heterochromatin occurs around the chromosome centromere and near telomeres.

Facultative heterochromatin
Genes that are silenced through a mechanism such as histone methylation or siRNA through RNAi produce facultative heterochromatin.

The regions of DNA packaged in facultative heterochromatin are not consistent between the cell types within a species, and thus a sequence in one cell that is packaged in facultative heterochromatin (and the genes within poorly expressed) may be packaged in euchromatin in another cell (and the genes within no longer silenced).

An example of facultative heterochromatin is X-chromosome inactivation in female mammals such as the cat in the image on the right: one X chromosome is packaged as facultative heterochromatin and silenced, while the other X chromosome is packaged as euchromatin and expressed. The black and orange alleles of a fur coloration gene reside on the X chromosome. For any given patch of fur, the inactivation of an X chromosome that carries one gene results in the fur color of the other, active gene.

Centric heterochromatin
Centric heterochromatin, a variety of heterochromatin, is a tightly packed form of DNA that is a constituent in the formation of active centromeres in most higher-order organisms; the domain exists on both mitotic and interphase chromosomes.

Centric heterochromatin is usually formed on alpha satellite DNA in humans; however, there have been cases where centric heterochromatin and centromeres have formed on originally euchromatin domains lacking alpha satellite DNA; this usually happens as a result of a chromosome breakage event and the formed centromere is called a neocentromere.

Centric heterochromatin domains are flanked by pericentric heterochromatin.

Acetyl groups
Acetylation (or in IUPAC nomenclature ethanoylation) describes a reaction that introduces an acetyl functional group into a chemical compound. (Deacetylation is the removal of the acetyl group.)

In histone acetylation and deacetylation, histone proteins are acetylated and deacetylated on lysine residues in the N-terminal tail as part of gene regulation. Typically, these reactions are catalyzed by enzymes with histone acetyltransferase (HAT) or histone deacetylase (HDAC) activity, although HATs and HDACs can modify the acetylation status of non-histone proteins as well.

There are "nearly 50,000 acetylated sites [punctate sites of modified histones] in the human genome that correlate with active transcription start sites and CpG islands and tend to cluster within gene-rich loci."

"[L]ysine acetylation almost always correlates with chromatin accessibility and transcriptional activity".

Methyl groups
Methylation is "the addition of a methyl group replacing a hydrogen atom.

DNA methylation in vertebrates typically occurs at CpG sites (cytosine-phosphate-guanine sites, that is, where a cytosine is directly followed by a guanine in the DNA sequence). This methylation results in the conversion of the cytosine to 5-methylcytosine. The formation of Me-CpG is catalyzed by the enzyme DNA methyltransferase. Human DNA has about 80%-90% of CpG sites methylated, but there are certain areas, known as CpG islands, that are GC-rich (made up of about 65% CG residues), wherein none are methylated. These are associated with the promoters of 56% of mammalian genes, including all ubiquitously expressed genes. One to two percent of the human genome are CpG clusters, and there is an inverse relationship between CpG methylation and transcriptional activity.

"Non-CpG methylation (CNG and CNN) ... has been observed at a low frequency in the early mouse embryo"

Protein methylation typically takes place on arginine or lysine amino acid residues in the protein sequence. Arginine can be methylated once (monomethylated arginine) or twice, with either both methyl groups on one terminal nitrogen (asymmetric dimethylated arginine) or one on both nitrogens (symmetric dimethylated arginine) by peptidylarginine methyltransferases (PRMTs). Lysine can be methylated once, twice or three times by lysine methyltransferases. Protein methylation has been most-studied in the histones. The transfer of methyl groups from S-adenosyl methionine to histones is catalyzed by enzymes known as histone methyltransferases. Histones that are methylated on certain residues can act epigenetically to repress or activate gene expression.

Phosphoryl groups
Phosphorylation is the addition of a phosphate (PO43-) group to a protein or other organic molecule.

Kinases phosphorylate proteins and phosphatases dephosphorylate proteins.

Reversible phosphorylation of proteins is an important regulatory mechanism that occurs in both prokaryotic and eukaryotic organisms.

Phosphoryl groups attach to histones at serine and threonine sites.

Ubiquityl groups
"The core histones that make up the nucleosome are subject to ... modifications, including ubiquitination [that occurs] primarily at specific positions within the amino-terminal histone tails."

Hypotheses

 * 1) The epigenome around A1BG is opened as if for any gene rather than a specific promoter, enhancer, or other transcription related factor.