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Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207575 | GEO | 2022/07/07

REPOSITORIES: GEO

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Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [RNA-seq]

Project description:Transcription factors (TFs) are classically attributed a modular construction, containing well-structured sequence specific DNA-binding domains (DBDs) paired with disordered activation domains (ADs) responsible for protein-protein interactions targeting cofactors or the core transcription initiation machinery. However, this simple division of labor model struggles to explain why TFs with identical DNA binding sequence specificity determined in vitro exhibit distinct binding profiles in vivo. The family of Hypoxia-Inducible Factors (HIFs) offer a stark example: aberrantly expressed in several cancer types, HIF-1α and HIF-2α subunit isoforms recognize the same DNA motif in vitro – the hypoxia response element (HRE) – but only share a subset of their target genes in vivo, while eliciting contrasting effects on cancer development and progression under certain circumstances. To probe the mechanisms mediating isoform-specific gene regulation, we used live cell single particle tracking (SPT) to investigate HIF nuclear dynamics and how they change upon genetic perturbation or drug treatment. We found that HIF-α subunits and their dimerization partner HIF-1β exhibit distinct diffusion and binding characteristics that are exquisitely sensitive to concentration and subunit stoichiometry. Using domain-swap variants, mutations, and a HIF-2α specific inhibitor, we found that although the DBD and dimerization domains are important, a major determinant of chromatin binding and diffusion behavior is dictated by the AD-containing intrinsically disordered regions (IDR). Using orthogonal genomic approaches such as Cut-and-Run and RNA-seq, we also confirmed IDR-dependent binding and activation for a specific subset of HIF-target genes. These findings reveal a previously unappreciated role of IDRs in regulating the TF search process that may play a role in selective functional target site binding on chromatin.

2022-07-08 | GSE207574 | GEO

Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [Cut&Run]

2022-07-08 | GSE207573 | GEO

Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [ChIP-seq]

Project description:We performed ChIP-seq to compare genome-wide HIF-1b and HIF-2a occupancy in wild type 786-O cells to 786-O cells with either HIF-1b or HIF-2a endogenously tagged with a V5-Halo moiety.

2021-10-29 | GSE183900 | GEO

Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors

Project description:Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors

| PRJNA856250 | ENA

Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [Cut&Run]

Project description:Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [Cut&Run]

| PRJNA856256 | ENA

Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [RNA-seq]

Project description:Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [RNA-seq]

| PRJNA856255 | ENA

Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [ChIP-seq]

Project description:Mechanisms Governing Target Search and Binding Dynamics of Hypoxia-Inducible Factors [ChIP-seq]

| PRJNA762306 | ENA

Target gene selectivity of hypoxia-inducible factor-alpha in renal cancer cells is conveyed by post-DNA-binding mechanisms.

Project description:Inactivation of the von Hippel-Lindau tumour suppressor in renal cell carcinoma (RCC) leads to failure of proteolytic regulation of the alpha subunits of hypoxia-inducible factor (HIF), constitutive upregulation of the HIF complex, and overexpression of HIF target genes. However, recent studies have indicated that in this setting, upregulation of the closely related HIF-alpha isoforms, HIF-1alpha and HIF-2alpha, have contrasting effects on tumour growth, and activate distinct sets of target genes. To pursue these findings, we sought to elucidate the mechanisms underlying target gene selectivity for HIF-1alpha and HIF-2alpha. Using chromatin immunoprecipitation to probe binding to hypoxia response elements in vivo, and expression of chimaeric molecules bearing reciprocal domain exchanges between HIF-1alpha and HIF-2alpha molecules, we show that selective activation of HIF-alpha target gene expression is not dependent on selective DNA-binding at the target locus, but depends on non-equivalent C-terminal portions of these molecules. Our data indicate that post-DNA binding mechanisms that are dissimilar for HIF-1alpha and HIF-2alpha determine target gene selectivity in RCC cells.

| S-EPMC2360163 | biostudies-literature

DNA methylation repels binding of hypoxia-inducible transcription factors to maintain tumour immunotolerance

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-06-18 | GSE85356 | GEO

Hypoxia, Hypoxia-Inducible Factors and Liver Fibrosis.

Project description:Liver fibrosis is a potentially reversible pathophysiological event, leading to excess deposition of extracellular matrix (ECM) components and taking place as the net result of liver fibrogenesis, a dynamic and highly integrated process occurring during chronic liver injury of any etiology. Liver fibrogenesis and fibrosis, together with chronic inflammatory response, are primarily involved in the progression of chronic liver diseases (CLD). As is well known, a major role in fibrogenesis and fibrosis is played by activated myofibroblasts (MFs), as well as by macrophages and other hepatic cell populations involved in CLD progression. In the present review, we will focus the attention on the emerging pathogenic role of hypoxia, hypoxia-inducible factors (HIFs) and related mediators in the fibrogenic progression of CLD.

| S-EPMC8305108 | biostudies-literature

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