Epigenetics & Gene Control

Tapping Into Unexplored Approaches In Therapies

Nature vs Nurture

Let’s take the example of identical twins, and each twin is raised by different families. We all know that identical twins to originate from the same DNA (deoxyribonucleic acid), means that their genetic markup has vast amounts of similarities. Now, one twin is raised differently than the other (in a different location, environment, education as well as diet and habits).

Decades later they reunite, aware that they are identical twins but are so different, with varying educational and professional background, as well as different hobbies and interests. Why is this so?

While these identical twins share very similar genes, their upbringing has influenced their state of mind, body, etc. to grow and become two very different persons. ‘Nature vs nurture’ paves the way to a deeper related subject, known as ‘epigenetics’ – influencing how our genes are expressed.

What is Epigenetics?

Epigenetics means ‘above’ or ‘on top of’ genetics. It studies how our DNA interacts with other molecules found within our cells which can ‘activate’ or ‘deactivate’ genes. In this case, epigenetics refers to external modifications to DNA that turn genes ‘on’ or ‘off.’ These modifications do not change the DNA sequence itself, but instead, they alter the physical structure of DNA, which affects how our cells ‘read’ genes.

Epigenetics is the reason why our skin cells are different from our brain cells or why our bone cells are different from our muscle cells. All our cells essentially contain the same DNA, but our genes are expressed differently (turned ‘on’ or ‘off’), which creates the different cell types.

Gene Expression 101

How does our gene work? How does it define the colour of our eyes, skin tone, physical and personal traits, etc.? To understand this, we must first understand how our genes are expressed, as it will ‘control’ how our cells differentiate and multiply.

Genes in our DNA are expressed in two stages: transcription and translation.

Transcription. In each of our cells, our DNA cannot leave the cell’s nucleus. Hence, it is unable to generate a protein on its own. The generation of proteins from our DNA coding sequence begins with a process called transcription. During transcription, several enzymes unwind DNA to provide access to another enzyme known as RNA (ribonucleic acid) polymerase. RNA polymerase travels along the unwound DNA strand to construct the mRNA molecule until it is ready to leave the nucleus.

Translation. Once mRNA exits the nucleus and enters the cytoplasm of the cell, it will find a ribosome so that the process of translation can begin. A pair of three nucleotide bases of the mRNA molecule is referred to as a codon, and each codon is specific for only one amino acid.

While our DNA serves as the ‘genetic blueprint’, our RNA passively converts these blueprints into proteins. There are 3 types of RNA:

1. Messenger RNA (mRNA) – carries the protein blueprint from a cell’s DNA to its ribosomes, which are the machines that drive protein synthesis.

2. Transfer RNA (tRNA) – carries the appropriate amino acids into the ribosome for inclusion in the new protein.

3. Ribosomal RNA (rRNA) – predominant molecules in our cells’ ribosome that builds protein molecules as it translates mRNA.

Zooming into Our Chromosomes for Gene Control

For DNA to fit within our cells, it is compacted and packaged (together with histones, a type of protein) in the nucleus of the cell as a substance called chromatin (the material that makes up our chromosomes). For our genes to be expressed, the chromatin needs to be ‘opened up’ so our DNA’s instructions can be read.

The chromatin regulatory system is responsible for the opening and closing of this chromatin, and hence impacts which genes express certain traits.

One example of an epigenetic change is DNA methylation, which is the addition of a methyl group (also known as ‘chemical caps’) to part of the DNA molecule. Chemical caps prevent certain genes from being expressed entirely.

Another example is acetylation or deacetylation of histones. Histones are proteins that DNA wraps around. Without histones, our DNA would be too long to fit within our cells. Acetylation can ‘relax’ the histones, making the DNA more accessible to proteins that ‘read’ genes. Deacetylation of histones, on the other hand, would ‘squeeze’ the DNA tightly, preventing it from being ‘read’ by our cells.

A third epigenetic mechanism is regulatory RNA. MicroRNAs (miRNAs) are small, noncoding sequences that are involved in gene expression. Thousands of miRNAs are known, and the extent of their involvement in epigenetic regulation is an area of ongoing research.

In short, epigenetic approaches in therapy, for instance, seeks to either suppress and silence, or even enhance and amplify gene expression.

Epigenetic Therapy

As the name implies, epigenetic therapy is the use of drugs or other epigenome-influencing techniques to treat medical conditions. Many diseases, including cancer, heart disease, diabetes, and mental illnesses are influenced by epigenetic mechanisms. Epigenetic therapy offers a potential way to influence those pathways directly.

Unlike gene therapy that is more ‘permanent’ and known to have inherent side-effects, epigenetic therapies are reversible. This means that we can treat patients with more cost-effective drug therapies.

Cancer. Epigenetics in cancer recently been the subject of intensive study. Recent key findings are that cancers frequently use epigenetic mechanisms to deactivate cellular antitumor systems and that most human cancers epigenetically activate oncogenes. Epigenetic therapy seeks to reverse the process by influencing patient cells to express more antitumor activity.

Diabetes. Scientists believe that the methylation of certain genes causes type 2 diabetes mellitus (T2DM). Due to genes being repressed, the body does not regulate blood sugar transport to cells, causing a high concentration of glucose in the bloodstream. One approach to epigenetic therapy for diabetes is to inhibit the methylation of such genes.

Cardiac dysfunction. A number of cardiac dysfunctions have been linked to cytosine (one of four main bases found in DNA & RNA) methylation patterns. Epigenetic treatment methods for cardiac dysfunction are still highly speculative. Small interfering RNA (siRNA) therapy targeting miRNAs are being investigated. The primary area of research in this field is on using epigenetic methods to increase the regeneration of cardiac tissues damaged by various diseases.

Gene Traffic ControlTM by Foghorn Therapeutics

Foghorn has recently developed the Gene Traffic ControlTM Product Platform that can precisely target and manipulate the chromatin regulatory system to develop therapies. Foghorn has already used the GTCTM Product Platform to develop new insights. It serves as a discovery engine that will simultaneously yield many additional targets. The company, currently in the pre-clinical stage, is rapidly advancing over 10 programs across a wide range of cancers and is beginning to explore other diseases.

Treatment of Rare Blood Cancers by Imago BioSciences

Imago is focused on an epigenetic enzyme, LSD1 (short for ‘lysine-specific demethylase 1’), that removes methyl groups from lysines on histones and other chromatin-bound proteins regulating transcription. The presence or absence of these ‘methyl marks’ at specific sites on proteins helps determine the properties and fate of blood cells. Mutated blood cells have altered patterns of gene expression which results in abnormal behaviour causing myeloproliferative disorders (a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow). The therapeutic goal is to restore normal patterns of gene expression and possibly eliminating the mutant cells that causes myelofibrosis, essential thrombocythemia, myelofibrosis, acute myeloid leukemia (AML), etc. Their most recent candidate bomedemstat has already entered Phase 2 clinical trials.