New mechanism of transcriptional regulators influences tumor development

The Wistar Institute scientists have discovered a novel mechanism of transcriptional regulation of cellular senescence that promotes the release of inflammatory molecules that, in turn, affect tumor growth by changing the surrounding microenvironment.

Wistar’s Dr Rugang Zhang (center) with lab members. Image Credit: The Wistar Institute.

According to the research, published in the Nature Cell Biology journal, methyltransferase-like 3 (METTL3) and 14 (METTL14) proteins serve as transcriptional regulators that help establish the senescence-associated secretory phenotype (SASP).

Cellular senescence refers to a steady state of growth arrest where cells cease dividing but stay viable and create a variety of growth-promoting and inflammatory molecules that are jointly known as SASP.

Such molecules are responsible for the complex interaction between senescent cells and adjacent cells, and also the impact of cellular senescence in a number of physiological diseases and processes.

While senescence is believed to be a powerful barrier to tumor development, the SASP performs a stage-dependent role during the development of tumors, regulating the removal of premalignant lesions at the time of initiation and encouraging the growth of developed tumors.

Senescent cells undergo widespread changes in gene expression needed to adapt their phenotype and functions. We pointed out a new mechanism that allows cells to turn on a set of genes encoding for the SASP molecules and may potentially be targeted to inhibit this aspect of senescence while preserving its antitumor function.”

Rugang Zhang, PhD, Deputy Director, The Wistar Institute Cancer Center

Zhang is also the Christopher M. Davis Professor and leader of the Immunology, Microenvironment & Metastasis Program.

Zhang, who is also the study senior author, and his research group targeted METTL3 and METTL14—proteins that chemically modify messenger RNA to control its activity. The team discovered a novel role of these proteins in senescence and control of gene expression that is independent of their RNA-altering function.

Depleting METTL3 and METTL14 cells showed decreased expression of SASP genes, like inflammatory cytokines, but had no impact on cell cycle arrest or other senescence markers. This indicates that reduced SASP is not an indirect outcome of the overall inhibition of senescence.

Our results indicate that METTL3 and METTL14 promote expression of SASP genes, in accordance with other studies that revealed an oncogenic role for these two proteins.”

Pingyu Liu, PhD, Study First Author and Staff Scientist, Zhang Lab

The researchers then examined the relationship of METTL14 and METTL3 with DNA, comparing both control and senescent cells. Although the two proteins collectively exist on DNA in control cells, they have different distribution patterns in senescent cells, wherein METTL3 sits upstream of SASP genes, close to the transcription start site, and METTL14 detaches from gene bodies, on regulatory elements known as enhancers.

The team demonstrated that METTL3 and METTL14 use this positioning pattern and interact with one another to bring two DNA sequences, which remain distant in non-senescent cells, closer together. This enables the formation of promoter-enhancer chromatin loops. As a result, the SASP gene expression is activated.

Although we focused on senescence, we envision that the transcription-regulating function of METTL3 and METTL14 may be involved in many other biological processes beyond our current study.”

Rugang Zhang, PhD, Deputy Director, The Wistar Institute Cancer Center