The MLL4 gene, also known as KMT2D, provides the blueprint for a protein that acts as a master regulator. This enzyme influences how other genes are turned on or off within our cells. This function is a fundamental process that directs the development and ongoing health of the body, ensuring that cells perform their correct functions at the appropriate times.
The Role of MLL4 in Gene Regulation
The function of the MLL4 protein is an example of epigenetics, which involves chemical marks added to our DNA. These marks guide cellular machinery on which genes to read without changing the DNA sequence itself. This system allows cells with the same DNA to develop into different types, like a heart or skin cell.
Inside each cell, DNA is tightly coiled around proteins called histones. This compact storage keeps most genes inaccessible. For a gene to be used, the DNA in its vicinity must be unwound so that the cellular machinery can read it.
MLL4 is a histone methyltransferase, an enzyme that places a small chemical tag called a methyl group onto a histone. This modification, known as H3K4 methylation, does not alter the DNA sequence but acts as a powerful signal.
When MLL4 adds a methyl group, it loosens the DNA’s grip on the histone. This creates an “on switch,” signaling that the nearby gene is now available to be expressed, or read. This process is important at regulatory regions of DNA called enhancers, which help activate genes from a distance.
MLL4’s Importance in Development and Bodily Functions
The gene-switching capability of MLL4 is necessary during embryonic development. As an embryo grows, MLL4 turns on the precise sets of genes needed to build the skeleton, form a functioning heart, shape facial features, and develop other organs. Without these timely genetic cues, development cannot proceed correctly.
This role extends to cell differentiation, where unspecialized stem cells are guided to become the many different cell types that make up the body. MLL4 helps direct this process by activating the specific genes that define each cell’s unique identity and function.
Even after birth and throughout adult life, MLL4 continues to perform functions. It plays a role in maintaining the health of the immune system, is involved in metabolic processes like the regulation of body fat, and contributes to normal brain function.
The Connection Between MLL4 Mutations and Kabuki Syndrome
When the MLL4 gene is altered by a mutation, it can disrupt the protein’s ability to regulate other genes. The most well-documented condition caused by these mutations is Kabuki syndrome, a developmental disorder affecting multiple parts of the body. The specific set of symptoms linked to MLL4 mutations is classified as Kabuki syndrome type 1.
Individuals with this syndrome often have distinct facial features, including long eye openings with everted lower lids, arched eyebrows, and a flattened nose tip. Kabuki syndrome is also associated with skeletal abnormalities, mild to moderate intellectual disabilities, growth delays that result in short stature, and heart defects.
The genetic mechanism is a concept known as haploinsufficiency. Humans inherit two copies of most genes, one from each parent. In Kabuki syndrome, an individual has one normal, functional copy of the MLL4 gene and one copy that is mutated and non-functional.
Having only a single working copy of the MLL4 gene is not enough for the body to produce a sufficient amount of the MLL4 protein. This 50% reduction in the protein’s availability leads to the widespread developmental problems seen in the syndrome.
MLL4’s Link to Cancer
In a different context, the MLL4 gene acts as a tumor suppressor. By controlling which genes are turned on, MLL4 helps regulate processes like cell growth and division. This function is a safeguard that prevents cells from growing in an uncontrolled manner, which is the hallmark of cancer.
When mutations occur in the MLL4 gene within specific cells during a person’s lifetime, this protective mechanism can be lost. Unlike the mutations that cause Kabuki syndrome, which are present from conception (germline mutations), these are acquired (somatic) mutations. The inactivation of MLL4 can remove the brakes on cell growth, contributing to tumor development.
This loss of MLL4 function has been identified in a variety of cancers. Researchers have found MLL4 mutations in certain types of blood cancers, such as non-Hodgkin lymphoma. These mutations are also seen in cases of bladder cancer and in medulloblastoma, a type of brain tumor common in children.
Current Research and Therapeutic Avenues
Scientific research continues to delve into the complexities of MLL4, aiming to create a complete map of all the genes it regulates. A deeper understanding of this genetic network will clarify how its disruption leads to conditions like Kabuki syndrome and cancer. This knowledge is a prerequisite for developing targeted treatments.
For Kabuki syndrome, research is exploring ways to compensate for the reduced amount of the MLL4 protein. One strategy involves using drugs that target other components of the cell’s epigenetic machinery, such as histone deacetylase (HDAC) inhibitors. This work remains in the early stages.
In oncology, the presence of MLL4 mutations in tumors presents a potential target for treatment. The development of “epigenetic drugs” is a promising area of cancer therapy designed to correct the gene expression patterns that have gone awry. For cancers driven by MLL4 inactivation, such therapies could potentially restore the normal controls on cell growth.