A recent international study published in Nature Communications examined how cells utilize the same histone variant in both the activation and suppression of gene expression, making a fascinating discovery with significant Hungarian contributions. Researchers from the University of Debrecen, Eötvös Loránd University, and the HCEMM-BRC Single-Cell Omics Advanced Core Facility in Szeged, headed by Dr. Zsuzsanna Darula, participated in this groundbreaking work.
Genetics as a science is surprisingly young: the DNA molecule’s iconic double-helix structure was first described only in 1953. This pivotal revelation ushered in decades of intensive research into how DNA functions and is regulated, ultimately leading, by the 1970s and ’80s, to advances with tangible impacts, from insulin production and forensic analyses to vaccine development.
This era kicked off the so-called biotechnology revolution. Today, schoolchildren learn that DNA encodes genetic information in genes, which cells transcribe into RNA and then translate into proteins. Proteins, in turn, define the nature of all living organisms, influencing everything from heart structure to venom glands, nails, horns, or suction cups.
However, these processes only make sense when considered alongside gene regulation. Molecular mechanisms ensure that the right genes turn on or off at precisely the right times. To transform a fertilized egg into a newborn infant, for instance, countless genes must be activated or silenced with precise timing.
We know that such regulation involves elements beyond the DNA’s coding sequence. This layer of control, epigenetics, can dramatically alter outcomes. In a honeybee colony, both queen and worker bees develop from the same genetic blueprint. The difference lies in how these genes are packaged and managed through epigenetic regulation. A single genome can thus give rise to strikingly different organisms.
This prompts the question: how does the cell control gene expression so effectively? One key factor is that DNA is not some “disembodied” code. It is a large molecule with length, width, and spatial constraints. It can coil, bend, or even break. Certain molecules can bind to it, making some regions inaccessible.
The recent study emerging through the collaboration of Hungarian laboratories and their foreign partners shed light on the enigmatic question of how the same epigenetic factor, a variant histone, can both increase and decrease the stability of the histone-containing particles the DNA is wound around, depending on their location in the genome.
Every human cell contains nearly two meters of DNA. Storing it efficiently is no small feat. Cells solve this by using assemblies of histone proteins called nucleosomes. Each nucleosome is made up of eight histone molecules fitting together like puzzle pieces to form a spool-like structure around which the DNA winds.
The nucleosomes line up like beads on a string, forming a long and well-organized histone-DNA complex called chromatin, compacting the genetic material to save space. The coin has two sides, though: DNA so stored is inaccessible. Genes stored this way remain “silent.”
Modifications of the histones and the DNA, and the presence or absence of variant histones in the different nucleosomes, regulate their stability and, simultaneously, the accessibility of the DNA wound around them. Before cell division, the entire histone-DNA content is tightly packed into the familiar chromosome shapes, facilitating proper division.
The researchers have found that a small “tail” region of a particular variant histone, H2A.Z, is key to controlling the stability of the nucleosomes containing this histone. This nine amino acid-long “tail,” named C9, critically influences whether histone holds onto the DNA or lets it unwind, making genes accessible again.
Even more exciting, the team discovered that removing C9 or reintroducing it can alter not only nucleosome behavior but the entire nuclear architecture. Because these manipulations are possible in living cells, this insight opens the door to potential medical applications.
By controlling the cell’s DNA packing and unpacking mechanisms, we might one day fine-tune gene expression patterns as a therapeutic strategy. This could be relevant for conditions linked to improper gene expression, such as cancer, autoimmune diseases, or even the aging process itself.
A crucial factor enabling the identification and measurement of changes in these histone proteins was the work carried out at the HCEMM-BRC Single-Cell Omics Advanced Core Facility. Researchers there used specific enzymes to break down the proteins of chromatin samples derived from cells with full-length and tail-less H2A.Z into peptides, followed by mass spectrometric analysis. Matching the data against a database allowed them to pinpoint which proteins and subunits were present.
This research marks a step toward understanding and potentially harnessing the cell’s intricate machinery for gene regulation. If DNA packing can be carefully managed, it may, one day, offer a new avenue for disease treatment, ushering in a future where controlling gene expression at will is not just the stuff of theory but a concrete clinical tool.
The Hungarian Center of Excellence for Molecular Medicine (HCEMM) is a distributed institute whose scientists develop advanced diagnostics and treatment options supporting healthy aging. Currently, the HCEMM program is funded by an H2020 Teaming Grant, where Semmelweis University, the University of Szeged and the Hun-Ren Biological Research Center, Szeged, cooperate with their advanced partner, the European Molecular Biology Laboratory (EMBL, headquartered in Heidelberg, Germany). The support of the Hungarian government is also essential for the operation of the HCEMM, primarily through the Thematic Excellence Program and the National Laboratories Program. HCEMM works at the interface of academic and industrial research on topics related to Translational Medicine. The goal is to improve the quality of life for an aging Hungarian population while at the same time lowering the cost of healthcare provision through novel applications in the field of molecular medicine. Coordination of the various activities is managed by HCEMM Nonprofit Kft., headquartered in Szeged, Hungary.
This article was first published in the Budapest Business Journal print issue of February 7, 2025.
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