A Review of the “Functional Genome” – Chapter 2
Genomic and Precision Medicine. DOI: http://dx.doi.org/10.1016/B978-0-12-800681-8.00002-5
A review of Chapter 2 entitled “The Functional Genome: Epigenetics and Epigenomics clearly states that there is evidence that the epigenome can be transmitted from parent to offspring, creating the potential for heritable transmission without modifying the genome sequence.
Commonly Modified Nucleotides
Chemically modified nucleotides are commonly expressed in the continuum of life and are thought to be limited to an addition of a methyl group to 5’ carbon in cytosine (5-methhylcytosine or 5mc) and then an addition of the hydroxy group to the methyl group to form 5-hydroxymethylcytosine (5hmC). This modification modifies the nucleotide and changes the physical capacity of cellular activity.
Cytosine is a part of DNA, as part of RNA, or as a part of a nucleotide. In DNA and RNA, cytosine is paired with guanine. It is inherently unstable, and can change into uracil creating a spontaneous deamination. This action can lead to a point mutation if not modified by DNA repair enzymes. (from Wikipedia).
Methylation and Cytosines
The methylation of cytosine occurs when DNA methyltransferase (DNMT) family of enzymes come into play. The DNMT’s transfer a methyl group to the 5’ carbon of cytosine residues in the genome. This methylation is thought to be of prime importance to the establishment of a modified genome.
Human cytosine methylation occurs very commonly when cytosine is followed by guanine in the genome. This junction is referred to as a CpG dinucleotide. To insure a better understanding of this biochemical expression, a review of that portion of the genome known as the heterochromatin must be sought.
Miller et al in Nature first identified 5mc in the literature in 1974. The genes in the heterochromatin are not generally expressed and 5mc was considered at that time to be an epigenetic mark that silences gene expression. That fact suddenly makes us aware that silencing of genetic material is a fact and that silencing of genetic information may play an integral role in the inability of pluripotent cells to differentiate into the precursor cells that will eventually produce the periodontal ligament (PDL) cells of the primary molar.
Silencing of Genetic Information
Silencing of a specific gene must be considered when the inquisitive observer seeks answers to specific oral disease that does not appear to have a chromosomal sequence etiology. Our present understanding of oral disease has often omitted the possibility that the epigenome may have a direct influence upon the creation of the basic anatomy of the primary molar.
We suggest that the loss of PDL precursor cells of the dental papilla impacts and silences the functional attributes of those cellular elements thus blocking the histologic formation of the PDL in the primary molar. The inability of the cellular elements to morph into those cells that create the PDL completely blocks the formation of the alveolar attachment leading to primary molar ankylosis (PMA).
This specific oral pediatric dental anomaly occurs very often in the primary dentition, almost exclusively in the first and second primary molars. The pathology is often expressed more fully in the second primary molar and requires close observation as the ankylosis becomes more evident in the late primary dentition.
A close examination of a periapical x-ray of an offending primary molar will disclose the lack of a periodontal ligament. The cemental structure of the root structure will be continuous with the alveolar bone. This lack of PDL creates an ankylosis that renders the primary molar unable to properly assume a normal occlusal relationship. As a consequence the first or second bicuspid is often displaced and unable to erupt into a normal occlusal relationship. Minimally affected primary molars may partially resorb and ultimately allow the eruption of the bicuspid into a delayed occlusal position.
Close observation of the periodontal status of all primary molars should be a positive requirement of recall appointments. Early identification and monitoring are essential elements in the treatment of PMA.