EPIGENETICS REPETITORIUM ... a thread

DNMT1 operates on hemimethylated CpG dinucleotides present in newly replicated DNA and restores symmetrical CpG methylation.

Heterochromatin emerges from a crosstalk between DNA methylation and histone deacetylases and methylatransferases.

Heterochromatin histone modifications & transcriptional silencing can be established even in the absence of DNA methylation. One has to be careful to interpret absenting CpG methylation without knowing histone modifications in the locus.

DNA methyltransferases (DNMTs) modify DNA, typically cytosine on carbon 5. Histones are methylated by at various lysine and arginine residues at their tails by various histone methyltransferases (HMTs). A lysine or arginine can receive up to three methyl groups

Multiple mechanisms suppress activity of mobile elements.

However, mobile elements ocassionally escape control mechanisms and disturb genome integrity. If this happens in the germline, changes in DNA sequence can be transmitted to future generations and exposed to natural selection.

Mobile elements explore every opportunity to avoid recognition and repression. Such windows of opportunity may come during global chromatin remodeling events in the germline.

Ocassionally, mobile elements acquire some positive novel role in the host organism - exemplified by evolution of syncytin or enhancer roles of long terminal repeats. Such events are called exaptations.

Relationship between mobile elements and their hosts is more intricate than parasitism. In some cases, like non-autonomous MaLR elements in mice, mobile elements blended so much into the control of endogenous gene expression that it's hard to see them as genomic parasites.

A boundary element can separate to distinct chromatin domains carrying "active" and "silent" histone marks. A classical example of an insulator separating two chromatin domains is CTCF protein.

"spreading" is a phenomenon where a particular histone modification affects neighboring nucleosomes.

Nucleosomal histones have tails exposed to the environment where they are accessible for interactions with proteins that either deposit specific chemical modifications (writers) or interact with them (readers). This "histone code" is a layer of management of accompanying DNA.

Histone acetylation contributes to "open chromatin" structure, which makes DNA more accessible for binding by transcription factors and transcriptional initiation.

Histone deacetylation has the opposite effect.

Multiple histone tail modifications can appear on one nucleosome. Some are more likely than others to occur simultaneously (like H3K4me3 & H3K9ac or H3K9me2 & H3K27me2/3 or H3K9me3 & H4K20me3) than others. Some are mutually exclusive (H3K9me3 and H3K9ac).

A nucleosome can be seen as an evolutionary adaptation enabling an extra layer of control over information encoded in DNA. Nucleosomes at gene promoters are particularly busy control hubs targeted by many regulatory mechanisms.

Some of the modifications of histone tails are actively maintained through replication and cell divisions - such modifications have potential to form lasting epigenetic memory.

In addition to "writers" and "readers" of modified histone tails, there are "erasers" exemplified by histone demethylases - "erasers" wipe out "epigenetic memory" recorded on histone tails.

However, histone modifications at specific loci may be resistant to epigenetic reprogramming by histone demethylases.

S-phase or replication dependent histones are produced in huge amounts upon entry into S-phase to supply nucleosomes for newly synthesised DNA.

Nucleosomes can slide along DNA, this repositioning can be actively controlled by ATP-dependent chromatin remodeling complexes.

Paternal genome in mouse 1-cell zygotes undergoes rapid active global DNA demethylation, which erases most of 5-methyl cytosines in the paternal genome. Only selected CpGs survive this erasure.

Transmissin of epigenetic information from one generation to another is error prone. Certainly much more than transmission of genetic information.

At the same time, some epigenetic memory is stable and lasts through many cell cycles. For example, X-inactivation, once established in early development, will faithfully maintain silencing of the same X chromosome in somatic cells for the rest of female's life.

Intronic repressive histone marks do not stop transcription by RNA polymerase II.

Transcription by RNA polymerase II can be interfered by another RNA polymerase II transcribing the same DNA in the opposite direction. This effect should be considered when studying relationship of two overlapping transcripts.

Heterochromatinization of mobile elements protects genome integrity. Multiple mechanisms evolved to recognize such elements and suppress them. Highly selective mechanisms involve, for example, small RNAs or selective transcriptional repressors exemplified by KRAB-ZNF family.

A common theme for chromatin modification during gene silencing is presence of large multiprotein complexes carrying different chromatin modifying enzymes executing, a sequence of effects, such as histone deacetylation (shown below), H3K9 methylation, and DNA methylation.

Protamines replace nucleosomes in the sperm nucleus, which results in tigh packaging of the paternal genome in the sperm head.

A sperm is essentially a vehicle delivering the packed DNA to the oocyte.

Nucleosome assembly is assisted by histone chaperones.

... enough procrastination for tonight ...