Beckwith-Wiedemann Syndrome (BWS)
A disease with underlying chromatin defects is Beckwith-Wiedemann syndrome (BWS). This disease is most closely associated with the mutation of imprinting genes on chromosome 11 and it is normally passed on through an autosomal dominant inheritance pattern. Like with other chromosome loci, two allele copies should be inherited: one from each parent. In the case of the IGF2 alleles, only one should be expressed. The paternal allele is the one that is normally expressed. This normally occurs through the inactivation of the maternal allele. The IGF2 locus consists of the IGF2 gene, an enhancer region, and an insulator region. The insulator region is called the ICR1, or imprinting control region. On the maternal copy, a protein called CTCF should bind to the insulator region on the chromosome. This binding prevents the activation of the IGF2 gene because it prevents the enhancer from turning on transcription of the gene. On the other hand, the insulator element on the paternal chromosome is methylated. This methylation prevents the CTCF protein from binding to the insulator. Because of this, the enhancer can work to turn the IGF2 gene on. With BWS cases, both copies of the IGF2 gene are expressed leading to symptoms such as fetal overgrowth, macroglossia (overgrowth of the tongue), abdominal wall defects, ear pits/creases, and organomegaly (overgrowth of the organs). There are a couple of reasons why the maternal copy of the IGF2 gene might become expressed rather than silenced. One reason is the hypermethylation of the insulator region of the maternal chromosome. It is hypothesized that the methylation is caused because of a DNA deletion in the insulator region that would normally allow for the binding of the CTCF protein. The methylation could also be due to a point mutation in insulator region, which would also cause issues in the binding of the CTCF protein [11].
Rett syndrome
Another disease related to chromatin structure and modification defects is Rett syndrome. Rett is a neurological development disorder that occurs mostly in females. Some symptoms associated with Rett are loss of hand coordination skills, mobility, and speech. It is also not uncommon to see growth and respiratory inadequacies and seizures [7]. Rett syndrome shows an X-linked dominant inheritance pattern and is a result of a mutation in methyl-CpG-binding protein 2 (MECP2); this protein is thought to silence the transcription of certain genes. The mutation of MECP2 leads to activation of genes that, under normal circumstances, would be silenced [13]. MECP2 does this by recognizing methylated DNA. Once the methylation is recognized, they recruit histone deacetylases to help with the condensation of the chromatin. The causes for abnormal MECP2 proteins are missense mutations. One of the possibilities for the mutation is located in the portion of the protein that is charged with binding to the methyl CpG and another is in the area that is responsible for the recruitment of the histone deacetylases. Either of these issues can result in the inability of the protein to bind to the correct regions of the DNA thus the inability of histone modifying complexes to cause repression of the gene. Another possibility is that MECP2 could bind to the correct area of the DNA, but lack the ability to recruit modifying complexes. Although researchers are unsure of the exact location in which these repression mechanisms work, observations have shown that it is a protein that is very common in the brain and may be important for the activity of neurons that are part of the central nervous system [5]. Researchers also believe that the activity of MECP2 is related to external signals such as membrane depolarization by calcium ions. In this context, calcium is the cause of phosphorylation of a serine residue that subsequently causes the freeing of MECP2 from a promoter region. The promoter discussed here is Bdnf. By removing the MECP2 from this region, transcription of neuronal genes can occur [13].
Facioscapulohumeral Muscular Dystrophy (FSHD)
The loss of repression complexes within the cells consequently leads to gene activation. This occurs in individuals with Facioscapulohumeral Muscular Dystrophy (FSHD). This disease shows an autosomal dominant inheritance pattern [3]. The symptoms experienced by those affected by FSDH include a progressive weakening of skeletal muscles, most notably in the face, shoulder blades, and upper arm areas. Eventually, other skeletal muscles in the body will weaken and become lost as well, as there are no treatments for this disease [6]. The modifications that cause this disease occur on the FSDH1 locus of chromosome 4. This locus normally has a pattern of repeat sequences that are over 3 kilo bases. These arrays are called D4Z4. The reduction of these repeats leads to FSDH, and the amount of reduction correlates to the severity of the disease. The number of repeats that occur within the DNA varies within populations. Most commonly, there are four to seven repeats in FSDH patients. However, more repeats will lead to a less severe form of the disease while less repeats, usually one to three, are associated with the most severe cases of the disease. The loss of D4Z4 repeats causes the chromatin structure to become less condensed, allowing for the up regulation of nearby genes [3]. Another hypothesis for this disease is that the D4Z4 repeats may have activating activities that, in normal individuals, are blocked due to the presence of an insulator known as S/MAR. This idea arose due to the observation that S/MAR is found in large quantities in the normal muscle cell precursors, myoblasts, but not in nearly as high quantities in the cells of patients with FSDH [10].
Coffin-Lowry syndrome (CLS)
A disease that is associated with both chromatin structure and skeletal defects is Coffin-Lowry syndrome (CLS). CLS is another X-linked dominant disease that is characterized by mental retardation, facial abnormalities, tapered fingers, and other progressive skeletal abnormalities [9]. CLS is caused by mutation of a gene that codes for RSK2, which is part of the ras-dependent MAPK signaling cascade. The mutation can be a result of the deletion of a nucleotide, but it can also be caused by a nonsense or missense mutation. The type of mutations appears to be related with the severity of the disease symptoms, with the missense mutation causing the least detrimental of the phenotypes. The RSK2 is seemingly important for the phosphorylation of serine 10 on histone H3, which is triggered by epidermal growth factor. The phosphorylation of this serine triggers a large amount of acetylation of the histone H3 proteins by histone acetyl transferases [5]. This acetylation can then in turn lead to chromatin decondensation as well causing further gene activity issues.
Immunodeficiency Centromeric instability Facial anomalies (ICF)
The previously discussed diseases above are all dominantly inherited; however, another disease caused by defects in chromatin structure called Immunodeficiency Centromeric instability Facial anomalies, or ICF is an autosomal recessive disorder. As the name implies, this abnormality causes immune deficiencies, facial abnormalities and chromosomal instability. This chromosomal instability is seen in the centromere of chromosomes 1, 9, or 16. This disorder is also characterized by mutation in DNMT3B, which is DNA methyltransferase 3B [4]. The mutations in these DNA methyltransferases are mostly missense mutations; therefore, it is believed that the activity of these enzymes is not completely impaired. However, these mutations lead to hypomethylation throughout the entire genome of the individual, although attributed to specific sequences. The centrosome instability, for example, is caused by the under-methylation of the alpha satellite regions [3]. Alpha satellite regions are regions of DNA that have highly repetitive short sections that tend to be rich in adenine and thymine [1]. The lack of proper amounts of methylation leads to the decondensation of pericentric heterochromatin. This decondenstion has effects on the amount of RNA produced from genes that involve immunological functioning and development. Not only do these genes not get silenced causing increased amounts of RNA produced from them, they also cause timing irregularities in replication. Normally, heterochromatic regions are replicated late in S-phase of the cell cycle. However, the lack of compaction of this chromatin causes them to replication much earlier. The DNMT3Bs are pertinent in preserving the proper timing of replication. Another result is that the length of S-phase overall is shortened as well. This is caused by an increase in the replication fork speed, which is the result of hypomethylation leaving the chromatin in a much less condensed state. This open chromatin is much more easily accessed by replication machinery [8].
Rubinstein-Taybi Syndrome
Whenever chromosome 16 undergoes a removal of a section of DNA that contains the CREBBP gene which resides on its short arm (p), a severe form of the disease called Rubinstein-Taybi syndrome can occur. This disease is the result of random mutations, although it can sometimes, but rarely, be passed to progeny in an autosomal dominant manner. The CREBBP gene encodes for the CREB binding protein which is critical for developing fetuses. This syndrome is most recognized with individuals with broad thumbs and stunted height. Individuals are highly prone to serious infections. In these severe cases of Rubinstein-Taybi syndrome, the majority of infants do not live past early childhood. Recent studies have shown that the CREB binding protein acts as a histone acetyltransferase (HAT). It can acetylate virtually every core histone. It has seen to acetylate even other proteins, including p53. The CREB binding protein has also been seen to play a role in coactivating factors of transcription. Scientists are extremely interested in researching this protein – especially those scientists looking for therapies for Rubinstein-Taybi syndrome [5].
Alpha Thalassemia
The ARTX gene resides on the X-chromosome. Mutations in this gene have shown the accompaniment of adverse DNA-methylation. The exact mechanism is unclear, but the structure of chromatin is changed and the ARTX protein is altered which controls the activity of the genes HBA1 and HBA2 . Patients with a lowered expression of the HBA1 and HBA2 genes are diagnosed as having the disorder called alpha thalassemia. These genes carry information needed for the production of the alpha globin-protein. This protein is a major component of hemoglobin. The severity of this disease depends on the amount of the alpha globin-protein is properly produced. The less severe, the greater the amount of this protein is properly produced and vice versa. Patients range from being severely anemic to not showing any symptoms. Mutations in the ARTX gene affect other genes as well, although the specificity of these genes has not been determined and published. The symptoms that result from the altered expression of these unknown genes has been documented as following: undeveloped sex organs in males, poor cognitive function in males, poor motor control in males, and abnormal facial features in both males and females. Both sexes can display wide set eyes, low positioned ears, tiny noses, and abnormally shaped mouths. Whenever these symptoms are expressed, this syndrome is more specifically called the alpha thalassemia x-linked intellectual disability syndrome and is more commonly expressed in males [2].
Edited by Ashley Lauren McPhee and Cheryl Ann Fleming