Constitutional heterochromatin domains are regions of DNA found in the chromosomes of eukaryotes. [2] Most constitutive heterochromatin is found in pericentromeric regions of chromosomes, but is also found at telomeres and throughout chromosomes. [2] Humans have significantly more constitutive heterochromatin on chromosomes 1, 9, 16, 19 and Y. [3] Constitutional heterochromatin is primarily composed of high copy number tandem repeats called satellite repeats, minisatellite and microsatellite repeats, and transposon repeats. In humans these regions make up about 200Mb, or 6.5% of the total human genome ., but their repetitive composition makes them difficult to sequence, so only short regions have been sequenced.
Visualization of Constitutional heterochromatin is possible using the C-banding technique . The regions that are darker are regions of constitutive heterochromatin. [4] Due to the highly condensed nature of DNA, heterochromatin is dark in colour.
Constitutional heterochromatin is not to be confused with alternative heterochromatin , which is less condensed, less stable and much less polymorphic , and which does not stain when using the C-banding technique.
Celebration
Constitutive heterochromatin is more commonly found at the periphery of the nucleus attached to the nuclear membrane. This concentrates the euchromatic DNA in the center of the nucleus where it can be actively transcribed. During mitosis it is believed that constitutive heterochromatin is essential for proper separation of sister chromatids and centromere function. [6] The repetitive sequences found in the pericentromere are not conserved in many species and are more dependent on epigenetic modifications for regulation, whereas telomeres show more conserved sequences.
Constitutional heterochromatin was thought to be relatively devoid of genes, but researchers have found more than 450 genes in the heterochromatic DNA of Drosophila melanogaster . [5] These regions are highly condensed and epigenetically modified to inhibit transcription. For genes to be transcribed, they must have a mechanism to overcome the silencing that occurs in the rest of the heterochromatin. There are several proposed models for how genes are expressed in these regions, including insulation, denial, integration, exploitation, and TE inhibition models.
When genes are placed near a region of constitutive heterochromatin, their transcription is usually silenced. This is known as a position-effect change and can lead to a mosaic phenotype .
Replication and Epigenetics
Constitutive heterochromatin replicates late in the S phase of the cell cycle and does not participate in meiosis.
Histone modification is one of the main ways that the cell condenses constitutive heterochromatin. [7] The three most common modifications in constitutive heterochromatin are histone hypoacetylation , histone H3-lis9 methylation ( H3K9 ), and cytosine methylation . These modifications are also found in other types of DNA, but much less frequently. Cytosine methylation is the most common type, although it is not found in all eukaryotes. Humans have increased methylation at the centromere and telomeres, which are composed of constitutive heterochromatin. These modifications can persist through both mitosis and meiosis and are genetic .
SUV39H1 is a histone methyltransferase that methylates H3K9, providing a binding site for heterochromatin protein 1 (HP1). HP1 is involved in the chromatin condensation process that makes DNA inaccessible for transcription.
diseases
Genetic disorders that result from mutations involving constitutive heterochromatin affect cell differentiation and are inherited in an autosomal recessive pattern. [6] Disorders include Roberts syndrome and ICF syndrome .
Some cancers are associated with anomalies in constitutive heterochromatin and proteins involved in its formation and maintenance. Breast cancer is associated with a deficiency in the HP1 alpha protein , whereas non-Hodgkin’s lymphoma is associated with hypomethylation of the genome, and especially of satellite regions.
