Abstract IA-017: Chromatin and gene transcription in hypoxia

Abstract

Abstract Oxygen is essential for the life of most multicellular organism and changes in oxygen availability have implications in physiological and pathophysiological conditions. In response to hypoxia (low oxygen availability) transcriptional changes are induced. The transcriptional response to hypoxia is mediated primarily by the Hypoxia Inducible Factor (HIF) family of transcription factors. HIFs are activated in hypoxia via inhibition of prolyl hydroxylases (PHDs), a group of molecular dioxygenases, which require oxygen for their activity. Whilst the role of HIFs in the transcriptional response to hypoxia is well characterized, little is known with regards to chromatin structure in low oxygen stress and how this coordinates the transcriptional response. It was recently shown that chromatin is sensitive to oxygen levels, with hypoxia altering histone methylation at hypoxia responsive genes via inhibition of specific JmjC histone demethylases. To further investigate chromatin structure and its role in hypoxia induced gene transcription, we have performed ATAC-seq and RNA-seq in human cancer cell lines in acute and prolonged hypoxia. We find that acute hypoxia leads to increased promoter accessibility at a subset of hypoxia inducible genes, and this mostly precedes changes in mRNA expression, with further changes in chromatin structure after prolonged hypoxia. In addition, ChIP-seq data on histone methylation marks (H3K4me and H3K36me3), revealed similar earlier patterns of genomic distribution. Furthermore, we dissected the impact of HIF in the observed changes using a chemical probe and specific HIF1beta depletion analysis of ATAC-seq. This work gives insights into the role of chromatin dynamics in regulating the transcriptional response to hypoxia and elucidating the mechanisms behind these changes may lead to targeted therapies for hypoxia driven diseases. Citation Format: Michael Batie, Julianty Frost, Sonia Rocha. Chromatin and gene transcription in hypoxia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-017.