An Imprinting Control Region (ICR) is a specialized segment of DNA that functions as a master regulator for a group of genes. These regions are a component of epigenetics, a system that manages gene activity without altering the DNA code. ICRs ensure that imprinted genes are expressed in a parent-of-origin specific manner. This regulation is established during the formation of sperm and egg cells for correct gene expression during development.
The Foundation of Genomic Imprinting
Genomic imprinting is an exception to the classical rules of Mendelian genetics. Typically, an individual inherits two active copies of every gene, one from each parent. However, imprinting dictates that for certain genes, only one of these two parental copies is switched on, meaning either the maternal or paternal copy is used exclusively.
This parent-specific gene expression is determined by epigenetic marks laid down in the parental germline—the sperm or egg cells. These marks “imprint” the gene, silencing one parent’s copy in the offspring.
There are over 200 known imprinted genes in humans, many of which are organized into clusters that are regulated together. This control over gene dosage is important for development. The imprints are erased and re-established in the germline of each new generation according to the individual’s sex.
How Imprinting Control Regions Work
The function of Imprinting Control Regions is rooted in DNA methylation. This process involves attaching small chemical tags, called methyl groups, to specific sites on the DNA. This methylation acts as a signal that can silence a gene, preventing the cellular machinery from reading its instructions. Whether an ICR is methylated is determined by its parental origin.
A protein involved in this process is called CTCF. When an ICR is unmethylated, CTCF can bind to it and act as an insulator. This creates a physical barrier that blocks communication between a gene and its enhancers—stretches of DNA that help activate gene expression.
An example of this mechanism is the H19/Igf2 locus on human chromosome 11. On the maternally inherited chromosome, the ICR is unmethylated, allowing CTCF to bind. This binding blocks enhancers from reaching the Igf2 gene, a growth promoter, keeping it silent, while the nearby H19 gene, a growth suppressor, is expressed.
Conversely, on the paternally inherited chromosome, the ICR is heavily methylated. This methylation prevents CTCF from binding, so it no longer acts as an insulator. The absence of the CTCF roadblock allows the shared enhancers to activate the Igf2 gene. The methylation on the ICR also directly silences the paternal copy of the H19 gene.
ICRs and Developmental Processes
The regulation managed by ICRs is important for healthy development, particularly during the fetal stages. Many imprinted genes controlled by these regions are involved in placental function and the regulation of fetal growth. This system balances the allocation of resources from the mother to the fetus. Paternally expressed genes tend to promote growth, while maternally expressed genes tend to restrict it, creating a regulated equilibrium.
For instance, the paternally expressed IGF2 gene is a major driver of fetal growth, while other maternally expressed genes act to constrain it. The function of ICRs is necessary to maintain this balance, supporting both placental development and appropriate fetal growth rates.
Beyond fetal growth, ICRs and the genes they regulate also have roles in brain development and postnatal behavior. Studies in mice have revealed that certain imprinted genes are involved in establishing maternal care behaviors. Others have been linked to the development of specific brain regions, with maternally expressed genes being important for the cortex, while paternally expressed genes are more involved in the hypothalamus.
When Imprinting Goes Wrong
Errors in the epigenetic marks within an Imprinting Control Region can disrupt the balanced expression of imprinted genes, leading to congenital disorders. These “imprinting defects” occur when an ICR that should be methylated is not, or vice versa. Such errors can cause both parental gene copies to be active or both to be silenced, altering the gene dosage required for normal development.
Beckwith-Wiedemann syndrome, an overgrowth disorder, is an example of ICR malfunction associated with defects at the ICRs on chromosome 11p15.5. Loss of methylation on the maternal ICR controlling the H19/IGF2 genes can activate the maternal copy of the growth-promoting IGF2 gene. This results in a double dose of IGF2 expression, contributing to macrosomia (large body size) and an increased risk of childhood cancers.
Another group of imprinting disorders involves a cluster of genes on chromosome 15q11-q13. If a deletion or an imprinting defect occurs on the paternally inherited chromosome in this region, it leads to Prader-Willi syndrome, characterized by hypotonia and developmental delay. Conversely, if the same defect occurs on the maternally inherited chromosome, it results in Angelman syndrome, a distinct neurodevelopmental disorder.