Photo: ZEISS Microscopy
Chromosomes undergo precise structural changes at a molecular level during the different phases of cell division. These changes occur at a high level of accuracy to prevent genome instability. Genome instability resulting from broken, missing, or rearranged chromosomes has been found to be the root cause of cell death, carcinogenesis, and congenital disorders. Studying genomic instability helps researchers identify the causes of cancer and may lead to new advancements in their diagnosis and treatment.
Scientists have been working for a long time to understand the role played by cohesin during meiotic cell division. Cohesins are important proteins for maintaining genome integrity as they ensure faithful chromosome segregation by holding sister chromatids together during meiosis. Now, in a new study conducted by scientists led by Professor Keun P. Kim from Chung-Ang University, South Korea, embryonic stem cells (ESCs) were studied to understand whether the meiosis-specific cohesin complex plays an active role during mitotic cell division, which is responsible for the growth and development of all cells. Their findings were published online on 3 March 2022 in Genome Biology.
ESCs show pluripotency or the potential to differentiate into every cell type in the body, and also have an unlimited capacity for self-renewal and a high tolerance for DNA damage stress. "However, we know little about how ESCs maintain genome integrity and cope with the chromosomal abnormalities and replication stresses that can occur during cell proliferation and differentiation," explains Prof. Kim. To bridge this knowledge gap, the team identified two cohesin factors, REC8 and STAG3, which are specifically expressed in ESCs. They studied the possible contribution of these meiotic components during mitotic cell divisions that are closely linked with the structure and organization of chromosomes in ESCs.
Based on the existing information about meiotic cohesins, the team used ESCs derived from mice to analyze the expression pattern of mitotic cohesin components. High-resolution 3D-SIM (Structured Illumination Microscopy) and functional analyses were employed to understand how REC8 and STAG3 contributed to chromosome structure and cellular function in mitotic divisions. The team found that if the amount of cohesin proteins in the cell is suppressed, the chromosomes exhibit severe compaction, resulting in their early non-separation—ultimately leading to an unstable genome. To prevent this crisis, it is necessary to maintain adequate levels of the cohesin factors REC8 and STAG3, which ensure chromosomal stabilization and adequate sister chromatid cohesion during the cell cycle in ESCs.
This study proves that chromosomal morphogenesis and interaction depend upon the presence or absence of mitotic and meiotic cohesin factors. The findings provide an improved understanding into the process of chromatid cohesion and chromosome formation in mitotic ESC chromosomes. Commenting on the applications of their study, Prof. Kim concludes: "The purpose of our study was to provide an answer for how the cohesin complex and other regulatory factors are involved in the formation of the chromosome and maintenance of genomic integrity. We think this will be helpful in researching the mechanisms and treatment methods of diseases like cancer, infertility, and chromosomal diseases such as Down syndrome."