title: Lactate induced HIF-1α-PRMT1 cross talk affects MHC I expression in monocytes.
abstract: Tumor infiltrating monocytes play a crucial role in tumor immune surveillance. As lactate is an important component of the tumor milieu, we investigated its role in the transcriptional regulation of MHC I which is crucial for mounting effective immune responses against tumors. Lactate elevated MHC class I expression in monocytes. Increase in HLAB expression was concomitant with increase in HIF-1α and decrease in PRMT1 levels. Interestingly, a reciprocal relationship was observed between PRMT1 and HIF-1α. While HIF-1α inhibition decreased lactate induced MHC I, both pharmacological inhibition and siRNA mediated knockdown of PRMT1 upregulated HLAB levels. PRMT1 over-expression rescued lactate mediated increase in MHC I expression. Lactate mediated changes in nucleosomal occupancy on HLAB promoter facilitated a chromatin landscape that favoured decreased recruitment of CREB and PRMT1 on CRE site of HLAB locus. The effect of lactate on the chromatin landscape of HLAB was completely mimicked by PRMT1 inhibitor AMI-1 in terms of nucleosomal occupancy and CREB recruitment. Besides demonstrating the importance of lactate in the transcriptional regulation of HLAB, this study highlights for the first time the (i) existence of HIF-1α-PRMT1 regulatory loop and (ii) role of PRMT1 in modulating chromatin landscape crucial for facilitating HLAB gene expression.
authors: National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana 122 051, India.
authors: Piyushi
authors: P
authors: Gupta
authors: National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana 122 051, India.
authors: Ankita
authors: A
authors: Singh
authors: National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana 122 051, India.
authors: Pruthvi
authors: P
authors: Gowda
authors: National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana 122 051, India.
authors: Sadashib
authors: S
authors: Ghosh
authors: National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana 122 051, India.
authors: Arpita
authors: A
authors: Chatterjee
authors: National Brain Research Centre, Nainwal Mode, NH-8, Manesar, Gurgaon, Haryana 122 051, India. Electronic address: ellora@nbrc.ac.in.
authors: Ellora
authors: E
authors: Sen
mesh_terms: D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D019344:Lactic Acid / Q000494:pharmacology*; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009707:Nucleosomes / Q000187:drug effects / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D015395:Histocompatibility Antigens Class I; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009707:Nucleosomes; D012097:Repressor Proteins; D019344:Lactic Acid; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases
keywords: HIF-1α; Lactate; MHC class I; Monocyte; PRMT1