Nuclear Enriched Abundant Transcript 1, or NEAT1, is a molecule residing within our cells. Unlike messenger RNAs (mRNAs) that carry instructions for building proteins, NEAT1 belongs to a class called long non-coding RNAs (lncRNAs). These lncRNAs do not code for proteins; instead, they act as sophisticated regulators and structural components. NEAT1 plays a role in maintaining cellular order and function.
Defining the NEAT1 Molecule
NEAT1 is found within the cell’s nucleus. This lncRNA exists in two primary forms, known as isoforms. The shorter isoform, NEAT1_1, is 3.7 kilobases long and possesses a poly-A tail.
The longer isoform, NEAT1_2, spans approximately 23 kilobases and lacks a poly-A tail. While both isoforms are present, NEAT1_2 has a unique architectural function that NEAT1_1 does not. NEAT1_1 has been observed in various non-paraspeckle locations, suggesting independent functions.
Building Cellular Structures Called Paraspeckles
The long NEAT1_2 isoform primarily forms nuclear bodies called paraspeckles. NEAT1_2 acts as a central scaffold, similar to the steel frame of a skyscraper, providing the foundational structure for these assemblies. Various proteins bind along the NEAT1_2 scaffold.
This assembly creates the ribonucleoprotein structure of a paraspeckle. Without NEAT1_2, paraspeckles cannot form, highlighting its indispensable role. These membraneless nuclear bodies form dynamically, allowing cells to respond to various cues.
Managing Cellular Stress and Gene Activity
Once formed, paraspeckles act as molecular “holding pens” within the nucleus. Their main function involves capturing and holding specific proteins and other RNA molecules, thereby preventing these molecules from carrying out their typical activities elsewhere. This process of sequestration is a form of gene regulation, influencing which genes are turned on or off. By holding onto certain molecules, paraspeckles can pause specific cellular activities, allowing the cell to focus its resources on dealing with a threat.
Paraspeckle formation and activity significantly increase when a cell is under stress, such as from a viral infection, exposure to toxins, or DNA damage. For example, proteasome inhibition, a type of cellular stress, leads to paraspeckle enlargement due to increased NEAT1 transcription. This enhanced sequestration helps the cell mount a controlled and effective response, contributing to cytoprotection and cellular survival under challenging conditions.
Role in Human Disease
The proper regulation of NEAT1 is connected to various human health outcomes, and its misregulation, whether too much or too little, is implicated in a range of conditions. In cancer, NEAT1’s role is complex and can be context-dependent. For instance, high levels of NEAT1 are frequently observed in many solid tumors, including lung, esophageal, colorectal, and hepatocellular carcinomas, where it often correlates with a less favorable prognosis by promoting tumor cell growth, migration, and resistance to therapies. In contrast, NEAT1 can be downregulated in acute promyelocytic leukemia, where it may function as a tumor suppressor by promoting cell differentiation.
NEAT1 also participates in the innate immune response, particularly against viruses. Following viral infections, such as by Hantaan virus, NEAT1 levels can increase, enhancing the production of antiviral genes like RIG-I and DDX60. This occurs by NEAT1 relocating the splicing factor SFPQ to paraspeckles, thereby releasing its repressive effect on the promoters of these antiviral genes.
Furthermore, abnormal NEAT1 and paraspeckle function have established links to neurodegenerative disorders. Elevated NEAT1 expression, particularly NEAT1_2, has been observed in the motor neurons of individuals with Amyotrophic Lateral Sclerosis (ALS) in early disease stages. While the precise nature of NEAT1’s contribution—whether protective or harmful—is still under investigation in these conditions, its dysregulation is also noted in other neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease.