Chromosome Shape: Longer Makes Wider

A new study challenges prevalent models of chromosome formation during mitotic cell division. The study compared the dimensions of chromosomes in yeasts and humans and found that not only is the width of chromosomes specific for the species, but within a species, chromosomal arms that are longer, are always wider.

The findings were published in Cell Reports “Chromosome arm length, and a species-specific determinant, define chromosome arm width”. Yasutaka Kakui, PhD, an assistant professor at Waseda University in Japan, Frank Uhlmann, PhD, a scientist at the Francis Crick Institute in the U.K., and Toru Hirota, PhD, chief of experimental pathology at the Japanese Foundation for Cancer Research are the senior authors of the study.

Kakui said, “Our findings would open a novel way to avoid chromosome miscarriage, a probable cause for the formation of cancer cells and/or birth defects such as Down syndrome, through controlling mitotic chromosome structure. This can potentially change medical treatments for cancer therapy and/or fertility treatments.”

Long strands of genomic DNA coil over histone protein scaffolds which supercoil and condense to form chromosomes during cell division. The compaction of threadlike meshes of chromatin into compact chromosomes ensures that genetic material is equally divided among daughter cells. However, the factors that control the shape of chromosomes—the dimensions and degree of DNA condensation—remain enigmatic.

Kakui was intrigued by how genomic DNA is stored within cells. “To expand our knowledge of how cells accurately pass on genetic information to successive generations, we need to understand the molecular basis for chromosome formation,” said Kakui.

Earlier studies showed that condensin, a large protein ring complex, plays a key role in chromosomal compaction during mitosis, by binding at specific sites on DNA and forming loops. Studies also showed that thicker chromosomes are more compact and that the pattern of condensin-binding sites is species-specific. However, the exact role of condensing and condensin-binding sites on DNA in determining chromosomal dimensions was unclear until now.

The researchers used Hi-C and super-resolution microscopy to analyze the correlation between mitotic chromatin contacts and chromosomal arm length in budding and fission yeasts. They showed that the distance between chromatin contacts is directly proportional to arm length during interphase and mitosis: shorter arms have short-range contacts and longer arms have long-range contacts. Moreover, they showed this correlation was species-specific.

When chromatin contacts are spaced wider apart on DNA, chromatin loops are larger. Both these parameters are indicators of wider chromosomal arms. Based on their studies on yeast species, the authors concluded that within a species, longer chromosomal arms were always wider.

They then extended their study to human cells, to examine the same correlations. “We made the unexpected discovery that longer chromosomal arms are always thicker throughout eukaryotic species, which helps us understand how mitotic chromosomes form during cell divisions,” said Kakui.

“It’s a fascinating result,” said Eric Kramer, PhD, a professor of physics at Bard College. (Kramer was not involved in the current study.) “While many of the protein families involved in chromosome compaction are now known, the way these proteins interact to shape the geometry of chromosome arms remains mysterious. The scaling result, that arm width increases with arm length, is very interesting, and reminiscent of recent work on cross-species comparisons.” In a paper published last year (“Scaling Laws for Mitotic Chromosomes”), Kramer’s team compared chromosome width in vertebrates and flowering plants to demonstrate that DNA content per unit volume is nearly constant and cross-sectional area increases with length.

The current study provides unique insights into mitotic chromosomal structure and compaction mechanisms that open new avenues of research for trisomy syndromes and cancer.