Linker Histone: The Golden Snitch of Cells!

Vaishnavi Kardale, Bioinformatics Centre, Savitribai Phule Pune University

DNA, probably one of the most famous bio-molecules, is a nucleic acid that carries information that gives us our unique identity. The DNA is present in the nucleus of our cells. Interestingly, the DNA has hundreds of millions of nucleotides carrying the genetic code of life. If the DNA is stretched out completely it can be as long as 6ft! This enormous bio-molecule needs to be fit in a microscopic cell. So, how does our cell do that?

Packaging of DNA:

In eukaryotic cells, the DNA is wrapped around positively charged proteins called histone proteins. In 1884, Albrecht Kossel isolated a peptone-like component from goose nuclei, which he decided to name as ‘histone’ and suggested that they are bound to nucleic acids. Using transmission electron microscopy, Woodcock and Olinses captured the first image of the chromatin popularly described as the ’bead on string’ motif. The DNA is wrapped around an octamer of 4 histone proteins H2A, H2B, H3, and H4. Later, experiments revealed that there are other histone proteins that are even more positively charged than the core proteins. This was the tripartite linker histone protein also known as the H1 protein. H1 protein occurs between the stretch of DNA that occurs between two nucleosomes called ‘linker DNA’. H1 association leads to stability of DNA.

Linker histone H1:

The linker histone H1 protein has a very high level of a positively charged amino acid lysine and therefore is one of the most positively charged proteins in the cell. Compared to the core histone proteins, the H1 protein is less tightly bound to the DNA and is prone to dissociation from chromatin in an ionic solution. H1 exists in various forms just like the core histone proteins. In mammals there are different types of H1 variants:

• somatic variants (H1.0-H1.5 and H1.X)
• Three testis-specific variants (H1t, H1T2, and H1LS1)
• Oocyte specific variant (H1oo)

These variations in H1 arise due to differences in the C and N terminal domain of H1.

In a review article published by Ankita Saha and Yamini Dalal from National Cancer Institute, NIH they compiled the H1 and its binding pattern that shape the epigenome in a normal and diseased cell.

H1 binding dynamics:

The determining factor of the affinity of the H1 towards the nucleosome is the structural component of H1- the C-terminal Domain. Fluorescence recovery after photobleaching (FRAP) experiments have shown that H1 that has the shortest CTDs stay on the nucleosome for the least amount of time. Post-translational modifications at CTD may alter the availability of this region for nucleosome binding. H1 exists as many variants in organisms and so it may prefer a different nucleosomal localization preference.

The initiation and progression of cancer are not independent of the genetic and epigenetic alterations of histone proteins. Altered H1 plays a key role in regulating chromatin state by controlling the formation of chromatin fibres. Mutations in HIST1H1B-E have been shown to cause follicular lymphoma. In a study with a cohort of 114 patients’ mutations were frequently observed in this gene family. The mutations were restricted to the DNA-binding CTD of the H1s. Another set of mutations in HIST1H1B-E led to the disruption of H1 function. 

H1 and cancer:

The levels of H1 in cells are correlated with the pathological status of the tumour. Under normal conditions, the H1.0 accumulates in the cell during tissue differentiation and aids the process of cellular senescence. This accumulative action of H1.0 is lost in cancerous cells leading to increased proliferative potential due to loss of senescence. On the other hand, a higher level of H1.5 is a marker for metastatic prostate cancer. The H1 genes are under very tight post-translational and post-transcriptional regulation. Studies have shown that to compensate for the loss of one H1 variant the cell starts overexpressing other variants. But as each variant has a different compaction ability, such changes lead to changes in the chromatin architecture. Many H1 modifications are also associated with neurodegenerative diseases. 

Initially thought to be a mere repressor, it is now known that H1 family proteins play a huge role in genome architecture. The authors describe the H1 dynamics as a high-intensity ‘Quidditch’ match in the nuclear forest, where H1 takes to form the ‘Golden Snitch’ that zips in and out and about the ‘Bludger’-chromatin remodelers and the ‘Quaffle’-transcription factors, where the fate is decided by the epigenetic game of accessibility and showing how a glitch in the snitch can have an impact on the epigenome.

Also read: Human genome from the sediments of Georgia Cave

Reference:

1. Saha, A., & Dalal, Y. (2021). A glitch in the snitch: The role of linker histone H1 in shaping the epigenome in normal and diseased cells. Open Biology, 11(8), 210124. https://doi.org/10.1098/rsob.210124

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Author info:

Vaishnavi Kardale is a master’s student at the Bioinformatics Centre, Savitribai Phule University. She is interested in protein folding mechanisms and wants to study them further.

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