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Science of Epigenetics: Lamarck was right after all
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Serving as a bridge between genotype and phenotype, epigenetics was first coined by Conrad Waddington as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being.” Epigenetics today is more specifically defined as the “stable, heritable, but potentially reversible modifications of gene expression that does not involve mutations in the DNA sequence.” Epigenetics has shifted our comprehension of inheritance in recognizing the fact that phenotype is not simply the result of preset genetics, and the environment is a key player in expression of inherited genes. We recall the story of how Jean-Baptiste Lamarck was ostracized and ridiculed for his theory of the inheritance of acquired characteristics, namely that giraffes developed a long neck to reach higher branches in years of draught. It turns out, Lamarck was right after all.
To begin to comprehend epigenetics, one must grasp the complex packaging of DNA and gene expression. In eukaryotes, DNA wraps around histone proteins to form the nucleosome. The nucleosome is made up of 147 base pairs of DNA and an octameric core of histones H2a, H2b, H3 and H4. The “bead on a string” nucleosome is compacted and stabilized further by linker H1 histone proteins. Factors regulating the chromatin structure play a role in gene regulation in multicellular development. Gene expression is the synthesis of a gene’s coded information into functional gene products, which determines an organism’s phenotype. Gene expression can be modulated at any step from the initiation of transcription to post-translation. Mechanisms that involve complex modifications of the chromosomal components and nuclear structures are referred to as epigenetic mechanisms of gene regulation.
Anthony M. DiGioia III,
Editor
Epigenetic mechanisms include DNA modification, histone modifications, nucleosome location and non-coding RNA. DNA modifications work to alter the physical properties of the chromatin fiber, which alter the higher-order structures. There has also been documentation where histone modifications stabilize binding partners to chromatin. Currently, the best-described modes of epigenetic gene regulation are DNA methylation and enzyme-powered modifications of post-translational N-terminal tails of core histones. DNA methylation refers to the addition of a methyl group to DNA at the C5 position of cytosine residues in CpG dinucleotides, which cluster into “islands.” Methylation of these CpG dinucleotides suppresses transcriptional gene expression and silences transposons. In normal cells, CpG islands are generally left unmethylated, although methylation of promoters may occur during development and tissue differentiation. These islands are highly methylated in the inactivated X chromosome in a female organism. Groundbreaking studies have shown that, although each cell has the same DNA, there is a vast difference in tissue phenotype as a result of epigenetic control where genes can be undermethylated in the tissue in which they are expressed. Studies have also shown the phenomenon of genomic imprinting in which an allele inherited from one parent is expressed and the allele from the other parent is silenced.
Since completion of Human Genome Project, there has been a large focus on genome-wide association studies to identify single nucleotide polymorphisms (SNPs) associated with particular diseases, but most have failed to show causation. Research today is shifting from genomics to epigenomics with the recognition that complex diseases and traits are identified by an inconsistent pattern of inheritance; they are not solely genetically predetermined.
Hind Sawand
Evidence of epigenetics has recently shown prevalence in joint-related diseases such as osteoarthritis (OA) and developmental dysplasia of the hip (DDH). OA, the most common joint disease, is influenced by two main factors: advancing age and chondrocyte function. As a complex disease, genetics alone provides limited understanding of disease susceptibility, which could be accounted for by epigenetic modulations. Several studies have shown epigenetics may play a role in the progression of OA. Examination of gene promoters in cartilage and chondrocytes has shown the importance of DNA methylation on gene expression and subsequent disease susceptibility. Growth differentiation factor 5 (GDF5), involved in the maintenance and repair of synovial joints, has a rs143383 C/T SNP that is associated with OA susceptibility, height, DDH and Achilles tendinopathy. OA susceptibility increases with even a slight reduction in GDF5. The rs143383 SNP causes a differential allelic expression (DAE) in cartilage and other joint tissues, where there is a reduction in the T allele compared to the C allele. The T allele is associated with OA. It has been noted that women who are homozygous for the C allele have a smaller chance of having knee OA in relation to women homozygous for the T allele. This DAE imbalance is comparatively due to DNA methylation, and the effect of the rs143383 SNP on GDF5 has been shown to be regulated epigenetically though DNA methylation.
Javad Parvizi
The etiology of DDH also does not appear to be simple, but rather multi-factorial involving both genetic and environmental etiologies. A 12-fold increase of DDH among first degree relatives of those affected by the disorder and high concordance rate between monozygotic (41%) compared to dizygotic (2.8%) twins strongly supports genetic transmission of DDH. Little is known about the mechanism by which the environment affects hip development.
A recent study at our institution attempted to probe the genetic basis of DDH. DNA from each of a 72-member, four generation family affected by DDH was retrieved and through whole exome sequencing, a genetic mutation was identified. One shared variant allele, rs3732378, which causes a threonine (polar) to methionine (non-polar) mutation at position 280 in the trans-membrane domain of CX3CR1 was believed to causation of DDH in this family at least. The latter protein is highly expressed in mesenchymal stem cells differentiating into chondrocytes and not expressed in differentiated chondrocytes. It is known to mediate cellular adhesive and migratory functions, however its effect on the development of the acetabular labrum has yet to be identified. By using Sanger sequencing, this variant was found to be present in the DNA of all severely affected individuals and obligate heterozygotes. However, not all unaffected individuals were free of the disease allele. DDH is multi-factorial with both genetic and epigenetic causes. The variant is required, but insufficient to cause the disease.
A continued investigation of DNA methylation and other epigenetic mechanisms in regulating gene expression and disease penetrance is crucial to understanding etiology of OA, DDH and other musculoskeletal conditions. Manipulating these mechanisms is fundamental for prevention and treatment of these conditions in the future, as truly exciting scientific events are unfolding that will affect the future of our profession.
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Disclosures: Parvizi a paid consultant for Zimmer, Smith&Nephew, 3M, Convatech, TissueGene, Ceramtec, Emovi, Cadence, Medtronic and Pfizer. Sawan has no relevant financial disclosures.