A new study explores the role of HDAC4 in cellular senescence and aging. Read on to learn more.
In this article:
- What is Senescence?
- How Does Senescence Impact Aging?
- What Are Histones?
- What Did the Researchers Do?
- What Is HDAC4?
- What Role Does HDAC4 Play in Cellular Senescence?
- How Do These Findings Contribute to Epigenetics?
HDAC4 Sheds New Light on Cellular Senescence and Aging
What is Senescence?
Senescence is an irreversible cellular state. Epigenetic reprogramming triggers cells to go into a state where they are no longer dividing, but not dying either.
Researchers often characterize it as a state of arrest where the cell cycle stops, and cells can no longer grow. Senescence offers a few evolutionary benefits like suppressing the proliferation of damaged cells (including cancer cells), but there’s also a downside.
How Does Senescence Impact Aging?
Cellular senescence and aging are not the same things, but they’re indeed intertwined. In fact, cellular senescence can be seen as a hallmark of aging. Over time, the accumulation of senescent cells can contribute to cellular dysfunction and aging.
Mitochondrial dysfunction, DNA damage, epigenetic dysregulation, and telomere damage can trigger senescence. Senescent cells can then cause inflammation and cell exhaustion, both of which contribute to the aging process.
What Are Histones?
Histones play a role in a cell’s cycle progression, conversion of DNA to RNA, and other developmental events. Structurally, DNA, and histones are wrapped together.
Histone deacetylases (HDAC) are enzymes that regulate how tight or loose histones are wrapped around DNA. Functionally, it also plays a role in DNA expression regulation.
Since HDAC plays a role in regulating a cell’s cycle progression, a group of nine researchers wanted to understand its role in regulating senescence and the aging process. After conducting a series of experiments, they published their results in bioRxiv in June 2020.
What Did the Researchers Do?
In their study, the researchers evaluated different class IIa HDAC expressions in different senescence and aging models. They examined the HDAC levels in skin and liver cells of 4-month old mice (young) and 25-month old mice (old).
They also examined the effects of knocking out the different HDAC in cells. From all of the HDACs, they found that HDAC4 plays a role in senescence regulation.
What Is HDAC4?
Histone deacetylase 4 (HDAC4) is a protein from class IIa of HDAC. Rather than binding with DNA directly, HDAC4 interacts with DNA through transcription factors.
What Role Does HDAC4 Play in Cellular Senescence?
After testing different HDACs, they found that HDAC4 is downregulated in all of the senescence and aging models. This prompted the researchers to explore further.
They didn’t only examine the presence and absence of HDAC4 but also examined the sequential effects of low HDAC4 levels. Here are some of their other findings:
- HDAC4 levels decrease in older cells (compared to younger cells).
- HDAC4 levels trigger the appearance of specific senescence markers and cell-cycle arrest. Including harmful cells, like melanoma cells.
- After HDAC4 removal, DNA damage increases in the first 48 hours and then more rapidly in the next 24 hours.
- HDAC4 removal inhibits cell proliferation. In their sample, most of the cells without HDAC4 did not launch the second mitosis.
- HDAC4 absence increases DNA lesion accumulation during replication. When replication occurs before the DNA lesions are repaired, it could lead to a DNA mutation.
- Low levels of HDAC4 activates retroviral origin (ERV) transcripts. ERV transcripts involve RNA, which can change the DNA genome by inserting copies of its genome.
Overall, an HDAC4 knock-out can lead to:
- Accumulation of replication stress and DNA damage
- Expression of inflammatory genes
These events may trigger senescence prematurely. Because of these findings, the research team believes that HDAC4 may actually play a role in maintaining the genome integrity and epigenome identity of cells.
In the absence of HDAC4, senescence can begin in both pre-transformed and transformed cells. They believe that HDAC4 can safeguard a cell’s integrity by preventing the activation of senescent genes and regulating the expression of inflammatory genes.
How Do These Findings Contribute to Epigenetics?
Understanding HDAC4’s role in maintaining epigenome identity broadens medical professionals’ understanding of aging and cellular senescence, especially in the field of epigenetics. Epigenetics focuses on changes in gene expression.
It also factors in external variables like lifestyle and its impact on gene expression, aging, and disease. These new findings on HDAC4 may hold the key to understanding age-related changes in gene expression.