“Uncoiled” Chromosomes: A Unique Perspective on the Determinants of Chromosomal Width

Chromosomes are a highly condensed form of DNA and are crucial for cell division. During mitosis, chromosomes ensure that genetic material is evenly distributed among daughter cells. Interestingly, the dimensions and degree of DNA condensation in mitotic chromosomes vary from organism to organism. How this is regulated – i.e. which factor governs mitotic chromosome formation and size – remains a mystery.

A team of researchers led by Dr. Yasutaka Kakui from Waseda Institute for Advanced Study, Waseda University; Frank Uhlmann at the Chromosome Segregation Laboratory, The Francis Crick Institute; and Toru Hirota, from the Division of Experimental Pathology at the Cancer Research Foundation of Japan’s Cancer Institute, set out to decode this conundrum.

How did it all start? For Kakui, it was his fascination with chromosomes that motivated him to undertake this research. “How is genomic DNA stored in cells? This is an old, unresolved question. To expand our knowledge of how cells accurately transmit genetic information to successive generations, we need to understand the molecular basis of chromosome formation..” And that’s what motivated this study, the results of which were published in Cell reports.

During mitosis, DNA undergoes significant compaction to form chromosomes. A large protein ring complex called condensin plays a key role in the compaction process. It binds to specific sites on DNA and compresses it by forming loops. Thus, scientists know that condensin is crucial for DNA compaction, which is closely related to chromosome size – thicker chromosomes being more compact. They also know that the pattern of condensin binding sites is species specific. But the exact role of condensin and chromatin contacts in chromosomal determination dimensions is not yet clear.

Researchers explored various facets of condensin and chromatin contacts to answer the questions posed. They used Hi-C and super-resolution microscopy to analyze the correlation between mitotic chromatin contacts and chromosome arm length in budding and fission yeasts, S.cerevisiae and S.pombe, respectively. Conclusive evidence has been found indicating that the distance between chromatin contacts is directly proportional to arm length in both interphase and mitosis. Therefore, the shorter arms have short-range contacts and the longer arms have long-range contacts. This turned out to be species specific.

Now, longer distances of chromatin contacts lead to larger chromatin loops, both of which are indicators of larger chromosome arms. The authors therefore studied both budding and fission yeasts to conclude that within a species, longer chromosome arms were always wider. Motivated by the successful observation in yeasts, they extended their study to human cells, to find the same correlations. “We made the unexpected discovery that longer chromosome arms are always thicker in eukaryotic species, which helps us understand how mitotic chromosomes form during cell division.“, explains Kakui. Their study would be the first to conclusively establish that the length of the chromosome arm determines the width of mitotic chromosomes.

This study provided unique insights into mitotic chromosomal structure that challenge current insights into mitotic chromosome formation. Kakui summarizes, “Our findings would open a new avenue to prevent chromosomal miscarriages, a likely cause of cancer cell formation and/or birth defects such as Down syndrome, by controlling the structure of mitotic chromosomes. This can potentially change medical treatments for cancer treatment and/or fertility treatments.

A transformation of chromosomal studies and interventions is underway!

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Reference

DOI: https://doi.org/10.1016/j.celrep.2022.111753

Authors: Yasutaka Kakui,^1,2,3 Christopher Barrington,⁴ Yoshiharu Kusano,⁶ Rahul Thadani,³ Todd Fallesen,⁵ Toru Hirota,⁶ and Frank Uhlmann³

Memberships:

¹Waseda Institute for Advanced Study, Waseda University, Tokyo

²Center for Advanced Biomedical Sciences, Waseda University, Tokyo,

³Chromosome Segregation Laboratory, The Francis Crick Institute, London
⁴Bioinformatics and Biostatistics Science Technology Platform, The Francis Crick Institute, London
⁵Advanced Science Technology Platform in Optical Microscopy, The Francis Crick Institute, London

⁶Division of Experimental Pathology, Cancer Institute of Japan Cancer Research Foundation, Tokyo

About Waseda University
Located in the heart of Tokyo, Waseda University is a leading private research university with a longstanding commitment to academic excellence, innovative research, and civic engagement locally and globally since 1882. University has produced many changemakers in its history, including nine prime ministers and many leaders in business, science and technology, literature, sports and film. Waseda maintains strong collaborations with overseas research institutes and is committed to advancing cutting-edge research and developing leaders capable of contributing to solving complex global social problems. The University has set a goal of achieving a zero-carbon campus by 2032, in line with the Sustainable Development Goals (SDGs) adopted by the United Nations in 2015.

To learn more about Waseda University, visit https://www.waseda.jp/top/en

About Dr. Yasutaka Kakui from Waseda University
Dr. Yasutaka Kakui is Assistant Professor at the Waseda Institute for Advanced Study, Waseda University, Japan. He is passionate about research on chromosomes, chromatin organization, meiosis and oocyte aging, with the aim of contributing to the development of evidence-based fertility treatments. He has numerous publications to his credit and an excellent citation score. Learn more about Dr. Kakui’s work here: https://www.waseda.jp/inst/wias/other-en/2020/04/01/6914/