Regulation Of HSP90AA1 Gene Expression In Heat Shock By Histone Lysine Demethylase KDM3A - Specific Phosphorylation

Heat shock response is an important biological mechanism against the stimulus (heat shock/cold shock/heavy metal etc.) from the environment. It is indispensable for the lives to survival from the changes from the environment. The induced heat shock proteins comprise the specific protein family that can be regulated under heat shock and can also play an important roles such as molecular chaperones in response to heat shock.Histone widely exists in the chromatin and tightly binds with the DNA. It is the most vital component of the chromatin and can regulate the gene transcription and the chromatin dynamics. Histone lysine (K) residues, which are modified by methyl- and acetyl-transferases, diversely regulate RNA synthesis. Unlike the ubiquitously activating effect of histone K acetylation, the effects of histone K methylation vary with the number of methyl groups added and with the position of these groups in the histone tails. Histone K demethylases (KDMs) counteract the activity of methyl-transferases and remove methyl group(s) from specific K residues in histones. KDM3A (also known as JHDM2A or JMJD1A) is an H3K9me2/1 demethylase. KDM3 A performs diverse functions via the regulation of its associated genes, which are involved in spermatogenesis, metabolism, cancers and cell differentiation. But the mechanisms of how the KDM3A regulate the target gene or the biological process were largely unknown and needed more study. In our previous study, the heat shock could induce several heat shock proteins but not under IFNgamma stimulus. And the difference between cell lines also needs more research.In our study, we found that the HSP90AA1 gene can be significantly induced under heat shock in Jurkat cells (immortalized line of human T lymphocyte cells). We did the RNA-seq of the mRNA transcriptome of the Jurkat with or without 1h heat shock to explorer the highly upregulated genes and their common functions. We then demonstrated that mitogen- and stress-activated protein kinase 1 (MSK1) specifically phosphorylates KDM3A at Ser264 (p-KDM3A), which is enriched in the regulatory regions of gene loci in the human genome by the ChIP-seq of the p-KDM3A. The p-KDM3A seems to bind on the motifs which mostly like the STAT1’s. p-KDM3A directly interacts with and is recruited by the transcription factor Stat1 to activate p-KDM3A target genes under heat shock conditions. The ChIP-reChIP assay showed that the p-KDM3A and the STAT1 bind together on the HSP90AA1 promoter. And the H3K9me2 modification can be largely removed from the promoter of the HSP90AA1. To our knowledge, this is the first evidence that a KDM can be modified via phosphorylation to determine its specific binding to target genes in response to thermal stress.