February 24, 2024

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Scientists reveal key mechanism that controls genetic activity inside cells

Scientists reveal key mechanism that controls genetic activity inside cells



Scientists reveal key mechanism that controls genetic activity inside cells.

Histone modifications are closely related to transcriptional regulation and participate in processes that determine cell fate, development, and disease. 

Recently, a research team discovered how trimethylation of histone third subunit lysine four (H3K4me3) determines when and how DNA is read and translated into protein in the cell.

On March 03, 2023, a major new study published today in the journal Nature reveals a “traffic light” mechanism that controls genetic activity in cells, a system that could be targeted by cancer drugs already in development. 

The study, “H3K4me3 regulates RNA polymerase II promoter-proximal pause-release,” describes how “epigenetic” changes in DNA structure act as a “stop-and-go” signal that determines whether a gene should be read.

Scientists reveal key mechanism that controls genetic activity inside cells

https://doi.org/10.1038/s41586-023-05780-8


The Genome’s “Dark Matter”

Unlike our genetic makeup, the world of epigenetics remains largely unexplored, known as the “dark matter” of the genome. 

Some new research has recently answered a longstanding fundamental question — how epigenetic proteins regulate transcription and the process of gene expression (the process by which our genes are read and translated into proteins).

In this new study, scientists at The Institute of Cancer Research, London, have revealed how a key epigenetic signal known as H3K4me3 determines when and how DNA is read and translated into proteins within our cells.


Textbook discovery

The study shows that H3K4me3 acts like a set of traffic lights that regulate the flow of cars on a busy road, ensuring that genes are transcribed and activated in a controlled manner at the correct time. 

Understanding how it functions in normal cells could provide new clues to the development of cancer and the role that disruptions in the regulation of gene activity play.

More than 20 years ago, scientists had discovered that the enzyme that places H3K4me3, a chemical tag added to DNA, on DNA is essential for normal cell development and has also been linked to leukemia, breast, bowel and pancreatic cancers. But despite years of research, scientists did not understand the role of this chemical tag until now.

According to the researchers, this new “textbook discovery” changes our understanding of:

  • How epigenetic proteins help regulate cell development and are involved in cancer
  •  How the process of gene expression – decoding DNA into functional proteins used by our bodies – is regulated
  • How blocking epigenetic proteins affects normal and cancer cells


H3K4me3 modification regulates gene expression

The new discovery could lead to a new cancer treatment that targets epigenetic “traffic lights” that block the activity of genes that can trigger cancer, the researchers say.

Epigenetics affects the activity or expression of genes without changing the underlying genetic code — for example, by adding or removing chemical marks or making modifications to DNA or the proteins that wrap it around it, called histones. Chemical modifications such as H3K4me3 (trimethylation of histone H3 lysine 4) can turn genes on or off and are frequently altered in cancer.

Using mouse stem cells and complex genetic and biochemical experiments in the lab, the researchers discovered that the H3K4me3 modification is critical for regulating how and when our genes are expressed. The team found that H3K4me3 acts like a traffic light at a busy intersection.

By regulating the flow of RNA polymerase II, a protein complex that reads and decodes DNA, H3K4me3 determines when gene expression should start and how fast it should go .

When it gives the green light, H3K4me3 allows RNA polymerase II to move along the DNA and transcribe it into RNA as it moves.

 But without H3K4me3, RNA polymerase II gets stuck at specific spots on the DNA, causing transcription to stall and slow down.

 Previous findings have shown that disrupting or altering H3K4me3 levels in cells is important for cancer development and affects response to therapy.


Significance

The researchers say the new findings provide a new understanding of epigenetics. 

This is a very exciting area of ​​cancer research, yet remains largely underexplored. 

Solved a 20-year-old puzzle by discovering how a well-known epigenetic modification controls gene expression. 

Because the enzyme that determines H3K4me3 levels in cells is frequently found mutated in cancer, the research may have implications for understanding and treating cancer. 

Only with a basic understanding of how genes and cells work can a fundamental understanding of what can go wrong to create future cancer treatments.

References:
https://doi.org/10.1038/s41586-023-05780-8

Scientists reveal key mechanism that controls genetic activity inside cells

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