Abstract
Recent studies have disclosed the function of enhancer RNAs (eRNAs), which are long non-coding RNAs transcribed from gene enhancer regions, in transcriptional regulation. However, it remains unclear whether eRNAs are involved in the regulation of human heme oxygenase-1 gene (HO-1) induction. Here, we report that multiple nuclear-enriched eRNAs are transcribed from the regions adjacent to two human HO-1 enhancers (i.e. the distal E2 and proximal E1 enhancers), and some of these eRNAs are induced by the oxidative stress-causing reagent diethyl maleate (DEM). We demonstrated that the expression of one forward direction (5′ to 3′) eRNA transcribed from the human HO-1 E2 enhancer region (named human HO-1enhancer RNA E2-3; hereafter called eRNA E2-3) was induced by DEM in an NRF2-dependent manner in HeLa cells. Conversely, knockdown of BACH1, a repressor of HO-1 transcription, further increased DEM-inducible eRNA E2-3 transcription as well as HO-1 expression. In addition, we showed that knockdown of eRNA E2-3 selectively down-regulated DEM-induced HO-1 expression. Furthermore, eRNA E2-3 knockdown attenuated DEM-induced Pol II binding to the promoter and E2 enhancer regions of HO-1 without affecting NRF2 recruitment to the E2 enhancer. These findings indicate that eRNAE2-3 is functional and is required for HO-1 induction.
Highlights
Heme, which is conserved from prokaryotes to eukaryotes, is a biological cofactor of hemoproteins, including hemoglobin and cytochrome c, which are involved in oxygen transport and electron transfer reactions, respectively [1]
To further investigate how enhancer RNAs (eRNAs) enhancer 2 (E2)-3 affects the expression of NRF2-regulated genes, we examined the expression of glutamate-cysteine ligase catalytic subunit (GCLC), solute carrier family 7 member 11 (SLC7A11), ferritin light polypeptide (FTL) and sequestosome 1 (SQSTM1) in eRNA E2-3-KD cells
We showed for the first time that the regions adjacent to the human heme oxygenase-1 gene (HO-1) enhancers were actively transcribed and that some of the transcripts were inducible in response to diethyl maleate (DEM)
Summary
Heme, which is conserved from prokaryotes to eukaryotes, is a biological cofactor of hemoproteins, including hemoglobin and cytochrome c, which are involved in oxygen transport and electron transfer reactions, respectively [1]. Because intracellular free heme is highly toxic to cells due to the Fenton reaction, excess heme (e.g. derived from intravascular hemolysis or increased in several diseases) causes cell damage, while the lack of it retards the biological function of hemoproteins [1]. The synthesis and degradation of heme are strictly controlled in cells [2]. Heme oxygenase (HO) catalyzes the oxidative degradation of heme into biliverdin, ferrous iron and carbon monoxide (CO) [3]. HO-1 has multiple biological roles, such as heme detoxification, iron recycling, oxidative stress response and regulation of inflammation [1,7,8]. HO-1 is thought to be a potential therapeutic target for many diseases
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