How 3-D Arrangement of DNA Helps Perpetuate the Species

February 26, 2019
Kevin Hattori

Researchers in the Technion’s Rappaport Faculty of Medicine are part of an international team that recently presented new findings about the organization of DNA during sperm formation and its implications on future organisms. The research, which was published in Nature Structural & Molecular Biology was conducted by Prof. Noam Kaplan and master’s student Haia Khoury from the Technion, in collaboration with colleagues at Cincinnati Children’s Hospital Medical Center. Leading the research at Cincinnati were Prof. Satoshi Namekawa and research student Kris Alvattam.

Professor Noam Kaplan is a Taub Fellow through the Leaders in Science and Technology Program.

The DNA in the living cell is packed, together with the proteins attached to it, in a molecular complex called chromatin. Although it may seem that the chromatin serves only as a packaging of genetic data within the DNA, the way in which the DNA is packed considerably influences cellular systems. For example, DNA that is tightly packed may become inaccessible to the biological machinery that reads the DNA, possibly leading to inactivation of genes encoded in that DNA sequence.  R

This current research examined the organization of the DNA during sperm development, a process known as spermatogenesis. Although spermatogenesis has been long studied, the way in which DNA is packed during this process has not been mapped in detail due to technological challenges. The Technion and Cincinnati researchers met this challenge by using a novel technology, called Hi-C, which combines experimental molecular biology with computational analysis to measure the spatial organization of DNA.

Each day, millions of sperm cells are created in the human male body. One of the critical stages in the formation of sperm cells is meiosis (cell division). Early in meiosis, DNA is drastically reorganized as the chromosomes condense in preparation of the upcoming cell division. Furthermore, these condensed chromosomes swap segments of DNA and in this way increase genetic variation.

Diagram: Changes in the organization of DNA during sperm development. Left to right: developing sperm cells (early meiosis), developing sperm cells (after meiosis) and mature sperm cells. Top row: microscopy image of cells where DNA is marked in black. Lower row: Hi-C interaction maps showing spatial structures of DNA (rectangular shapes). In early meiosis when the DNA is condensed, the DNA structures exist but are weaker, then gradually strengthen after meiosis and in the mature sperm cells.

The research team successfully isolated mouse sperm cells at the start of meiosis when the chromosomes are condensed and then used Hi-C to measure the spatial organization of the DNA. The researchers discovered that the spatial structure of the chromatin gradually strengthens during spermatogenesis, until it reaches its ultimate strength in the mature sperm. They suggest that this organization enables the sperm cells to activate a wide variety of genes during meiosis, enabling the cells to later gain the unique ability of producing all cell types after fertilization. According to Dr. Kaplan, “In the future, we intend to use this approach to understand how the genome’s spatial structure may influence fertility.”

Prof. Kaplan joined the Technion Rappaport Faculty of Medicine in 2016 and established an interdisciplinary laboratory for studying the spatial structure and function of genomes in health and disease. He is a Taub Fellow through the Leaders in Science and Technology Program.

Haia Khoury

Haia Khoury completed her bachelor’s degree at the Technion’s Faculty of Biology and is currently pursuing a master’s degree in Biomedical Sciences at the Technion’s Rappaport Faculty of Medicine.

This research was funded by the National Institutes of Health (NIH) and the  Azrieli Foundation.

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