Biology subjects

Batie, M.

Publications and source records attributed to Batie, M..

10 recordsLinked to original sources

bioRxiv2026

Phosphorylation at S345 Converts HIF-2α from a Transcription Factor to an RNA binding protein

Oxygen sensing and adaptation are vital for metazoan survival. At the cellular level the response to hypoxia is characterised by a switch in transcriptional programming, primarily mediated by hypoxia-inducible factors (HIFs). HIFs comprise an obligatory heterodimer between an oxygen-sensitive HIF- subunit and an oxygen-insensitive HIF-1{beta} subunit, which together regulate gene expression in response to hypoxia. Among the three HIF- proteins in vertebrates (HIF-1, HIF-2, and HIF-3), post-translational modifications (PTMs) play a crucial role in modulating their stability, localisation, and activity. While many modifications have been investigated on HIF-1, our knowledge of HIF-2 regulation is very limited. Here, we investigated the function of the recently identified HIF-2 S345 phosphorylation site and demonstrate that this disrupts the interaction between HIF-2 and HIF-1{beta}, thereby silencing the HIF-2 transcriptional response. Additionally, our findings suggest that this modification redirects HIF-2 from its normal transcription factor function towards a role in mRNA fate control, as indicated by mass spectrometry interactome analysis and RNA-immunoprecipitation. Our discoveries highlight a new regulatory mechanism of HIF-2 activity, where S345 phosphorylation impedes HIF-2/HIF-1{beta} heterodimer formation, creating a switch in HIF-2 function. As HIF-2 is the only HIF- isoform with a clinically approved inhibitor, these insights are crucial for advancing therapeutic strategies targeting hypoxia signalling.

molecular biology↗

bioRxiv2026

KDM2B controls HIF levels and activity through its JmjC and CxxC domains

Hypoxia-inducible factors (HIFs) are key regulators of cellular responses to low oxygen (hypoxia), controlling the expression of genes required for survival and adaptation. KDM2B, a chromatin-modifying enzyme, is a direct target of HIF-1, but its precise role in regulating HIF and the hypoxia response remains unclear. Here, we investigated the role of KDM2B in the response to hypoxia in a variety of cell lines. Our analysis reveals that KDM2B depletion regulates HIF activity in a cell type-dependent manner, with KDM2B depletion decreasing HIF activity in U2OS and MDA-MB-231 cells and increasing HIF activity in HeLa cells. We show that KDM2B depletion also reduces HIF-1 protein and RNA expression and reduces HIF-1 binding at hypoxia-response elements of its target genes in U2OS and MDA-MB-231 cells. Conversely, overexpression of KDM2B enhances HIF activity and HIF-1 levels in both U2OS and HEK293 cells. Mechanistically, we find that KDM2B requires its JmjC demethylase and CxxC DNA-binding domains for HIF regulation. Furthermore, we demonstrate that KDM2B is required for RNA Pol II recruitment to the promoter of HIF1A. At the cellular level, KDM2B supports cell proliferation, with its depletion impairing proliferation and reducing cell numbers under hypoxic conditions. Our work highlights a new function of KDM2B as a key regulator of HIF-1 expression, acting through its demethylase and DNA-binding functions. Our data indicate that KDM2B is essential for cellular adaptation to hypoxia, impacting both HIF-dependent gene expression and cell survival, and has important implications for our understanding of HIF regulation.

molecular biology↗

bioRxiv2025

NRF2 upregulation by CDDO-Me protects AC16 human cardiomyocytes against doxorubicin-induced toxicity.

Doxorubicin (DOX) is an effective anticancer therapeutic but exhibits dose-dependent, potentially life-threatening cardiotoxicity. The specific mechanisms driving this cardiotoxicity are not fully understood but can include the induction of oxidative stress and subsequent cell death mechanism activation. This has prompted the exploration of NRF2, a master co-ordinator of antioxidant and largely cytoprotective pathways, as a potential approach for the alleviation of DOX-induced cardiotoxicity. Here, NRF2 was pharmacologically activated via CDDO-Me (hitherto referred to as CDDO) to reduce the negative consequences on AC16 human cardiomyocyte cell health and functions. NRF2 intracellular dynamics were quantitatively measured using live-cell imaging, demonstrating rapid ([~]10 min) yet sustained ([≥]24 h) induction of NRF2 expression and functional downstream activity. Genetic perturbations of the NRF2-KEAP1 system highlight that CDDO acts specifically through NRF2 to exert AC16 cytoprotection from DOX whilst not promoting human lung and pancreatic cancer cell line viability. Via RNA-seq analysis, we reveal that CDDO dampens DOX-mediated effects on p53 signalling, apoptosis and ferroptosis. This study provides novel insight into NRF2 dynamics in the widely utilised AC16 cells whilst further elucidating the molecular mechanisms contributing to DOX cardiotoxicity and potential NRF2-orchestrated defence. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=106 SRC="FIGDIR/small/675420v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@18c0bb5org.highwire.dtl.DTLVardef@154c707org.highwire.dtl.DTLVardef@d6c127org.highwire.dtl.DTLVardef@122ef0d_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

NF-κB is a Central Regulator of Hypoxia-Induced Gene Expression

Hypoxia is both a physiological and pathological signal in cells. Changes in gene expression play a critical role in the cellular response to hypoxia, enabling cells to adapt to reduced oxygen availability. These changes are primarily mediated by the HIF family of transcription factors, however other transcription factors such as NF-{kappa}B, are also activated by hypoxia. Although NF-{kappa}B is known to be activated by hypoxia, the extent to which NF-{kappa}B contributes to the hypoxic response remains poorly understood. Here, we analysed hypoxia-induced, NF-{kappa}B-dependent gene expression, to define the NF-{kappa}B-dependent hypoxic signature. Our analysis reveals that most genes downregulated by hypoxia require NF-{kappa}B for their repression. We show that although the NF-{kappa}B-mediated hypoxic response may vary between cell types, a core subset of hypoxia-inducible genes requires NF-{kappa}B across multiple cell backgrounds. We demonstrate that NF-{kappa}B is critical for reactive oxygen species (ROS) generation and regulation of genes involved in oxidative phosphorylation under hypoxia. This work highlights NF-{kappa}Bs central role in the hypoxia response and offering new insights into gene expression regulation by hypoxia and NF-{kappa}B.

molecular biology↗

bioRxiv2022

Regulation of Chromatin Accessibility by hypoxia and HIF

Reduced oxygen availability (hypoxia) can act as a signalling cue in physiological processes such as development, but also in pathological conditions such as cancer or ischaemic disease. As such, understanding how cells and organisms respond to hypoxia is of great importance. The family of transcription factors called Hypoxia Inducible Factors (HIFs) coordinate a transcriptional programme required for survival and adaptation to hypoxia. The effects of hypoxia and HIF on the chromatin accessibility landscape are still unclear. Here, using genome wide mapping of chromatin accessibility via ATAC-seq, we find hypoxia induces loci specific changes in chromatin accessibility enriched at hypoxia transcriptionally responsive genes. These changes are predominantly HIF dependent, reversible upon reoxygenation and partially mimicked by chemical HIF stabilisation independent of molecular dioxygenase inhibition. This work demonstrates that indeed, HIF stabilisation is necessary and sufficient to alter chromatin accessibility in hypoxia, with implications for our understanding of gene expression regulation by hypoxia and HIF.

molecular biology↗

bioRxiv2019

Adaptive thermogenesis in mice requires adipocyte light-sensing via Opsin 3

Almost all life forms can decode light information for adaptive advantage. Examples include the visual system, where photoreceptor signals are interpreted as images, and the circadian system, where light entrains a physiological clock. Here we describe a local, non-visual light response in mice that employs encephalopsin (OPN3, a 480 nm, blue light responsive opsin) to regulate the function of adipocytes. Germ line null and adipocyte-specific conditional null mice show a deficit in thermogenesis that is phenocopied in mice under blue-light deficient conditions. We show that blue light stimulation of adipocytes activates hormone sensitive lipase, the rate limiting enzyme in the lipolysis pathway, and that this is OPN3-dependent. Opn3 adipocyte conditional null mice also use reduced levels of fat mass when fasted and cold exposed further suggesting a lipolysis deficit. These data suggest the hypothesis that in mice, a local, OPN3-dependent light response in adipocytes is a mechanism for regulation of energy homeostasis.

physiology↗

bioRxiv2019

Hypoxia induces rapid changes to histone methylation reprogramming chromatin for the cellular response

Molecular dioxygenases include JmjC-containing histone demethylases and PHD enzymes, but only PHDs are considered to be molecular oxygen sensors in cells. Although, it is known that hypoxia can alter chromatin, whether this is a direct effect on histone demethylases or due to hypoxia induced HIF-dependent transcriptional changes is not known. Here, we report that hypoxia induces a rapid and HIF-independent alteration to a variety of histone methylation marks. Genomic locations of H3K4me3 and H3K36me3 following short hypoxia predict the hypoxia gene signature observed several hours later in cells. We show that KDM5A inactivation mimics hypoxic changes to H3K4me3 in its targets and is required for the cellular response to hypoxia. Our results demonstrate a direct link between oxygen sensing and chromatin changes via KDM inhibition.\n\nOne Sentence SummaryRapid oxygen sensing by chromatin

biochemistry↗

bioRxiv2018

An adipocyte light-Opsin 3 pathway regulates the circadian clock and energy balance.

Almost all life forms can detect and decode light information for adaptive advantage. Examples include the visual system, where photoreceptor signals are processed into virtual images, and the circadian system, where light entrains a physiological clock. Here we describe a pathway in mice that employs encephalopsin (OPN3, a 480 nm light responsive opsin) to mediate light responses in murine adipocytes. The adipocyte light-OPN3 pathway regulates neonatal growth in mice and is required for at least three important functions including (1) photoentrainment of a local circadian clock, (2) extracellular matrix deposition, and (3) regulation of mitochondrial content and the proportion of \"brite\" adipocytes. Furthermore, we show that the light-OPN3 pathway is required for normal levels of uncoupling protein 1 (UCP1) in white and brown adipose tissue. Consequently, neonatal Opn3 germ-line and adipocyte-conditional null mice show a reduced ability to maintain their body temperature under cold stress. This was also observed in wild-type mice deprived of blue light. We hypothesize that the adipocyte light-OPN3 pathway provides a dynamically responsive, circadian clock-integrated mechanism for regulating adipocyte function and in turn directing metabolism to thermogenesis rather than anabolism. These data indicate an important role for peripheral light sensing in mammals and may have broad implications for human health given the unnatural lighting conditions in which we live.

physiology↗

bioRxiv2017

SINHCAF/FAM60A links SIN3A function to the hypoxia response and its levels are predictive of cancer patient survival

The SIN3A-HDAC complex is a master transcriptional repressor, required for development but often deregulated in disease. Here, we report that the recently identified new component of this complex, SINHCAF/FAM60A, links the SIN3A-HDAC co-repressor complex function to the hypoxia response. SINHCAF Chromatin Immunoprecipitation-sequencing and gene expression analysis reveal a signature associated with the activation of the hypoxia response. We show that SINHCAF specifically repress HIF 2 mRNA and protein expression resulting in functional cellular changes in in-vitro angiogenesis, and proliferation. Analysis of patient datasets demonstrates that SINHCAF and HIF 2 mRNA levels are inversely correlated and predict contrasting outcomes for patient survival in both colon and lung cancer. This relationship is also observed in a mouse model of colon cancer, indicating an evolutionary conserved mechanism. Our analysis reveals an unexpected link between SINHCAF and cancer cell signalling via regulation of the hypoxia response that is predictive of poor patient outcome.

molecular biology↗

bioRxiv2017

Role Of Chymotrypsin-Like Elastase 1 In Lung Physiology And in α1-Antitrypsin Deficiency

1-antitrypsin (AAT) deficiency-related emphysema is the fourth leading indication for lung transplantation. We previously demonstrated that AAT covalently neutralizes chymotrypsin-like elastase 1 (Cela1) in vitro, that Cela1 is expressed during the alveolar stage of lung development in association with regions of lung elastin remodeling, and that lung stretch increases Cela1 expression and binding to lung elastin. Here we show that Cela1 is exclusively responsible for stretch-inducible lung elastase activity, reduces postnatal lung elastance, and is required for emphysema in an antisense oligo model of AAT deficiency. Cela1 mRNA is present in the human lung, and in the placental mammal lineage, Cela1 is more conserved than Cela2 or Cela3 with unique promoter and protein elements indicating a unique role for Cela1 in this lineage. These data demonstrate an adaptive role for Cela1 in placental mammal lung biology with physiologic relevance to AAT-deficient lung disease in humans.

physiology↗