DNA: Coding Vs. NON-Coding

The completion of the Human Genome Project in 2003 revealed a big surprise: up to 98% of the DNA making up the human genome does not code for proteins! The notion that parts of the genome were non-coding had been circulating for several decades, but when the actual percentage was confirmed it blew the industry’s mind. This discovery prompted the launch of a multi-year, international effort called Project ENCODE (ENCylopedia Of DNA Elements), with a goal to decipher the role of these non-coding regions.

It turns out most of the non-coding DNA plays a role in regulating when and how often coding regions are used. For cells to carry out their specialized function, specific genes must be “turned on” or expressed, while others must be “turned off.” Defects in the regulation of gene expression (making too much or not enough of a particular protein, or making it at the wrong time) are linked to a number of different diseases. In this WEEKLY, we will examine some key concepts behind gene regulation and its association with disease.

Terms of the Week: Regulome & Enhancers

The regulome consists of the parts of the genome that do not directly code for proteins—these non-coding parts essentially regulate when the protein-coding regions are used.

DNA that codes for regulatory RNA, such as microRNA, is one component of the regulome. Other components are DNA sequences called enhancers. Enhancer sequences are recognized by proteins that activate the expression of associated genes—in other words, they act to “turn on” an intended gene.

The Regulome & Disease

Genome-wide association studies, to identify common mutations in disease populations versus healthy populations, have been a research focus for the past several years. Far from being confined to protein-coding regions, it turns out most of these disease-associated mutations—93% of single base changes or SNPs—are actually contained within in the regulatory regions (the regulome). Astonishing!

In Development: Syros Pharmaceuticals

Syros Pharmaceuticals (Watertown, MA) was born out of the discovery of so-called super-enhancers—regions of DNA that activate gene expression, but are 10 to 100 times longer than typical enhancer sequences. Though less common in the genome, they manage to bind to a larger percentage of proteins responsible for activating gene expression—suggesting super-enhancers play a key role in regulating genes that define and control cell identity.

After identifying these zones of DNA, the company founders went on to demonstrate a large percentage of the disease-associate mutations found in the regulome are contained in the super-enhancer regions.

This discovery opens up the door for a new class of therapeutics dubbed “transcriptional therapeutics.” The moniker is derived from the first step of gene expression: transcription, or converting the information in DNA to RNA, which is then converted to the encoded protein.

The company is currently conducting preclinical trials on an inhibitor of the protein CDK7, which plays an important role in activating the expression of genes required for cell division. Early work has shown small molecule inhibition of CDK7—which binds a super-enhancer associated with a gene driving blood cancer—resulted in reduced expression of that gene. The data look most promising for leukemia and lymphoma.

In addition to cancer, the company plans to focus on the role of super-enhancers and gene regulation in inflammatory disorders as well as genetic disorders of the central nervous system and kidney.

Easily Confused: Genetics vs. Genomics

Genetics is the study of how traits are passed from one generation to the next, such as the BRCA1 gene conferring an inherited risk of breast and ovarian cancer. Genomics is the study of gene sequences, gene expression, and of the interaction of genes with each other and with regulatory elements.

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