Deoxyribonucleic acid, or DNA, is often termed the blueprint of all life on Earth. Packed away in the nuclei of most cells, the genetic information stored in DNA contains instructions for all the functions, structures, and hereditary information of a living organism.
Packing chromosomal DNA
Chromosomal DNA is immensely long for something so small; some studies put human DNA at around two metres in length, and all of that is packed tightly into a cell’s nucleus. In order to fit all that chromosomal DNA, it adopts a “beads-on-a-string” approach. The strands of chromosomal DNA are tightly wrapped around proteins known as histones, and together they form a nucleosome (which are the “beads”). These nucleosomes then come together to form chromatin fibres. After further winding, these chromatin fibres form the chromatid of a chromosome.
Genetic instructions are relayed through a process known as DNA transcription – during which an enzyme unravels the double helix structure of DNA during the transcription process, “reads” the template DNA strand and builds a ribonucleic acid (RNA) strand that now contains the genetic instructions from the original DNA strand. However, the transcription process requires chromatin to be unpacked from its highly condensed form in order for it to be easily “read.” How compact the chromatin is packed is determined by the chemical modifications of amino acids of the histone proteins.
Histone modifications
A team of researchers led by Prof Lars Nordenskiöld (NTU) and Prof Claus S. Sørensen (University of Copenhagen) examined a methylation (a type of chemical modification) pathway of the amino acid lysine 20 in histone H4 (H4K20): mono-methylation (H4K20me1). This methylation pathway is facilitated by a group of enzymes known as histone methyltransferases (also known as SET8), which help to add methyl groups ( to amino acids such as lysine. These SET8 enzymes are known to be involved in multiple biological processes; from replicating DNA to repairing it. Read full paper: Histone H4 lysine 20 mono-methylation directly facilitates chromatin openness and promotes transcription of housekeeping genes.
Left to right: Dr Shi Xiangyan, Dr Chen Qinming, Prof Lars Nordenskiöld
The new role of H4K20me1
In the past, the general H4K20 methylation pathway was usually associated with the maintenance of compact chromatin states. However, the researchers have described a different role for H4K20me1: rather than keeping chromatin compact, it instead facilitates chromatin openness – and therefore accessibility – by disrupting chromatin folding. It was discovered that H4K20me1 exists in significant amounts in actively transcribing gene bodies – places where there are open chromatin states – which contradicts H4K20me1’s previously ascribed role. The team also found that genes with greater levels of H4K20me1 also had greater levels of chromatin accessibility than genes with lower levels of H4K20me1, showing that H4K20me1 affects chromatin compaction states.
The importance of examining histone protein modification
The functions of a cell and its ability to thrive are based on numerous factors, one of which is how well the instructions coded within its chromosomal DNA can be transcribed and be passed from its nucleus. The team from NTU has demonstrated how H4 lysine 20 methylation affects chromatin accessibility and the transcription process, and that any disruption to it will affect overall genomic stability and cellular functions. The information from this study can therefore help in the designing of future treatments for diseases that are related to genomic problems associated with malfunctioning H4K20 methylation, such as some cancers as well as developmental growth disorders.