Signals can activate specific genes to control various biological processes. Most genes respond to previously experienced signals similarly to the first response. However, certain genes respond to previously experienced signals more robustly. This phenomenon is termed as transcriptional memory.

The proinflammatory cytokine tumor necrosis factor-α (TNF-α) activates nuclear factor-κB (NF-κB) pathway and plays a vital role in the pathogenesis of chronic inflammatory diseases. Targeted inhibition of TNF-α has achieved remarkable therapeutic success in patients with chronic inflammation. Does the key cytokine TNF-α mediate transcriptional memory? If so, what is mechanism? Which epigenetic enzymes and chromatin modifications play determinant roles in the establishment of mammalian transcriptional memory? Moreover, what differentiates genes with or without transcriptional memory effects?

In a study published in eLife, Dr. ZHU Bing's group at Institute of Biophysics of the Chinese Academy of Sciences discovered that sustained TNF-α stimulation can induce transcriptional memory, which offers faster, stronger and more sensitive subsequent TNF-α response for certain memory genes. This TNF-α mediated transcriptional memory is dependent on signal induced transcription factor activation and active DNA demethylation.

Using HEK293F cells containing an integrated DNA methylation silenced reporter gene as a model system, the researchers found that sustained TNF-α stimulation can induce the transcriptional memory of the reporter gene, which stimulates stronger and faster induction in the subsequent TNF-α stimulation.

They then identified a series of endogenous genes exhibiting TNF-α mediated transcriptional memory. Among them, the best endogenous memory gene is CALCB, which encodes the migraine therapeutic target calcitonin gene-related peptide (CGRP).

Besides, the researchers found that the DNA demethylation of the transcription factor NF-κB occupied genomic regions is accompanied with the establishment of the transcriptional memory, and in the ten-eleven translocation (TET) triple knockout (TKO) cells, which are depleted of active DNA demethylation, all the memory genes lost the TNF-α mediated transcriptional memory effect. These data suggested that active DNA demethylation is indispensable for consolidating transcriptional memory.

However, not all the NF-κB target genes exhibit transcriptional memory in response to TNF-α induction. High CpG density and initial methylation levels around the NF-κB binding sites correlate with the functional potential to serve as transcriptional memory modules.

For a few memory genes (e.g., CALCB), the memory consolidated cells can achieve a better induction with a 125-fold lower TNF-α concentration (0.4 ng/mL) than naive cells treated with 50 ng/mL TNF-α. This data suggested that the establishment of transcriptional memory could significantly elevates the cells' sensitivity to the inflammatory signal. This phenomenon may benefit the understanding for the transition from acute to chronic inflammation.

This study discovered the inflammatory cytokine TNF-α induced transcriptional memory, which is dependent on NF-κB pathway and active DNA demethylation. This is likely a general principle that can be applied to other signaling systems. Also, the study offers a pipeline to systematically identify genes with transcriptional memory.