Scientists Find That Genes May Prevail in the 'Physiological Cycle'

Comment: For instance, if we take the neural network as the structure, human life as the timeline, and gene construction as events, where time is projected onto events and events encounter time, then by performing functional analysis based on time series, what is there about life and death that is unknowable? Human activities have a 24-hour rhythmic cycle. It was previously thought that only a few genes and proteins are periodically turned on and off, but according to a recent report by Phys.org, American scientists have discovered that thousands of genes in various organs of the body also exhibit predictable daily fluctuations, and their activity cycles are controlled by various complex mechanisms. The relevant paper has been published on the website of the journal Science. Understanding how genes are periodically turned on and off throughout the day is key to mastering many physiological functions, including sleep and metabolism. Joseph Takahashi, a researcher at the Howard Hughes Medical Institute and the University of Texas Southwestern Medical Center, discovered rhythm genes and their protein products in the 1990s. He and other researchers identified the gene as CLOCK and found that two other proteins, BMAL1 and NPAS2, can bind to genes during the day to activate them. Additionally, four other rhythm regulatory factors, PER1, PER2, CRY1, and CRY2, can inhibit genes at night. The new study aims to comprehensively understand how activators and inhibitors coordinate to jointly maintain the body's 24-hour physiological rhythm. The core finding of the new study is that the function of RNA polymerase (the enzyme required for genes to transcribe and synthesize proteins) changes with the physiological rhythm. Takahashi said, "The initiation of RNA polymerase II marks the beginning of the cyclic rhythm of the entire genome. With the overall regulation of RNA polymerase II and transcription, the state of all chromatin is regulated by the rhythm circadian clock. Histones are also widely modified according to the rhythm of the entire genome, and histones are key to maintaining DNA integrity. This suggests that every gene may be modified according to the cycle of the physiological rhythm." Furthermore, they made many other important discoveries. First, rhythm regulatory factors can bind to many genomic loci and target genes. They studied the genome of mouse liver cells and found that over 20,000 loci can bind with one or more regulatory factors; among them, over 1,000 loci can bind with all seven regulatory factors, while many other loci can only bind with either activator or inhibitor factors. Takahashi said, "We previously thought that they all only bind to the same locus." Second, they studied the daily expression patterns of all genes in liver cells and found that during transcription, gene expression is not entirely controlled at the transcriptional level. They also discovered that the binding of RNA polymerase II to genes occurs earlier than gene transcription during the day. At the beginning of the cycle, the transcriptional activators CLOCK and BMAL1 recruited RNA polymerase II, but were subsequently inhibited by the appearing inhibitor CRY1. As a result, RNA polymerase had to "pause" for several hours, and transcription only began after the pause was lifted. Therefore, the physiological rhythm is not only related to RNA polymerase but also to the release of the "pause" state. "The targets of these rhythm genes, at the highest level, are metabolic pathways, so the circadian clock secretly controls daily metabolism. These discoveries provide new avenues for studying short-term transcription dynamics, physiological cycles, polymerases, and general transcription," Takahashi said. The next step is to study how RNA polymerase is controlled throughout the daily rhythm, what causes the polymerase to pause at specific times of the day for certain genes, and how other RNA molecules are regulated after transcription.