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Organization of Mammalian Genome

Unlike linear sequences, genomes are more complex. Their physiological properties are strongly influenced by the structure of their cells ...
Unlike linear sequences, genomes are more complex. Their physiological properties are strongly influenced by the structure of their cells, which in turn determines their functional properties in vivo. For gene transcription, DNA replication, and DNA repair, nearly two meters of genomic material in every human cell nucleus has to be folded into small spaces. It emphasizes the importance of maintaining physical chromosome organization at all times during any activity and governing genome organization during any activity. These molecular techniques can provide information about genome structure and functions, such as fluorescence in situ hybridization (FISH). As a result of recent technological advances, we can now study the folded state of an entire genome and possibly even identify the molecular machines that determine its shape.

The pus of wounded soldiers contained a new protein, discovered by Friedrich Miescher in 1869.

Each human has 46 DNA molecules, called chromosomes. Chromosomes 1 through 22 are numbered consecutively (autosomes), and males and females are differentiated by their sex chromosomes. There are over 6 billion letters in each of these molecules and when joined would be over 2 meters long. To fit inside a nucleus with a diameter of around a micrometer, the genome must be extensively packaged.




A eukaryotic genome's higher-order structure within a cell's nucleus is elaborate and dynamic. Understanding the relationship between genome structure and function requires a comprehensive understanding of the physical principles and molecular mechanisms underpinning its 3D organization. In this direction, sophisticated microscopy techniques, chromosome conformation capture, and analyses based on polymer models play a critical role. Resulting from these efforts, we explain the relationship between structure and function at different organizational levels of the genome.

Genetic material in an organism is contained in linear DNA sequences called genomes. The human genome project had the goal of determining the base pairs that make up human DNA, which comprises 3 billion base pairs. Although the human genome has produced a wealth of information, it now seems clear that the sequence of DNA base pairs does not determine the cellular function of the genome. A large part of the genome's function lies in its three-dimensional (3D) structure, which consists of meters long DNA enclosed within the limited volume of a cell nucleus of just a few micrometers.

A majority of the nucleus volume is taken up by DNA, while cellular factors involved in reading, copying, modifying, and maintaining the genome occupy the remainder. A sophisticated pattern in cellular function is derived when genetic information in packaged DNA is accessed by cellular factors that are organized and active in the nucleus of the cell. A nucleus does not contain transcription, replication, or recombination factories, where transcription, translation, repair, and recombination occur. Through an increasingly integrated approach that combines state-of-the-art microscopy and conformation capture techniques with polymer theory and simulations, we are discovering the 3D structure of the genome and the physical principles associated with its folding. Figure shows a diagram showing the hierarchical level of organizational structure, with which these studies were conducted and the key insights gained.


The packaging of eukaryotic double-stranded DNA (e.g., in humans, two meters long) within a micrometer-sized cell. As shown in the figure, primary, secondary and tertiary organization levels make up this process.

The nucleus of a cell is a complex arrangement of cellular factors responsible for reading, copying, and maintaining the genetic information. RNA-processing factors, transcription factors, and chromatin proteins, among others, are compartmentalized in the nucleus, which directs the activities of transcription and replication. An elaborate architectural environment within which genomes must act is created by the organizational properties of genomes and the mechanisms that act upon them.

A cell's genome functions are organized at three levels of hierarchical organization: nuclear processes themselves, such as transcription, RNA processing, DNA replication, and DNA repair; chromatin organization into higher-order domains; and chromosome orientation within the nucleus. Each of these levels has regulation potential, and they are all interconnected. The spatial compartmentalization of many nuclear processes is a defining characteristic. Nuclear events do not occur everywhere within the nucleus, but are rather confined to specific locations and usually occur within dedicated nuclear bodies. Incredibly, some of the fundamental, vastly different nuclear processes appear to be governed by similar mechanisms.
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Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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