Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

Peeters, Janneke G. C.; Picavet, Lucas W.; Coenen, Samuel; Mauthe, Mario; Vervoort, Stephin J.; Mocholí, Enric; Heus, Cecilia de; Klumperman, Judith; Vastert, Sebastiaan J.; Reggiori, Fulvio; Coffer, Paul J.; Mokrý, Michal; Loosdregt, Jorg van

doi:10.1080/15548627.2018.1509608

Cited by 36 publications

(22 citation statements)

References 60 publications

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“…In HeLa cells, starvation led to a reduction of H2B monoubiquitination on autophagy genes, resulting in activation of autophagy . A recent high‐throughput ChIP‐seq and RNA‐seq‐based study conducted in the human HAP1 line (Chronic myeloid leukemia cells), indicated that indeed, upon starvation, transcription of many autophagy genes is increased and this increase is associated with concomitant establishment of activating histone modifications and RNA‐Pol II recruitment . Histone demethylases have also been implicated in autophagy regulation.…”

Section: Epigenetic Control Of Autophagymentioning

confidence: 99%

Stress – (self) eating: Epigenetic regulation of autophagy in response to psychological stress

Puri

Subramanyam

2019

The FEBS Journal

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Autophagy is a constitutive and cytoprotective catabolic process. Aberrations in autophagy lead to a multitude of degenerative disorders, with neurodegeneration being one of the most widely studied autophagy‐related disorders. While the field has largely been focusing on the cytosolic constituents and processes of autophagy, recent studies are increasingly appreciating the role of chromatin modifications and epigenetic regulation in autophagy maintenance. Autophagy has been implicated in the regulation of neurogenesis, and disruption of neurogenesis in response to psychological stress is a proximal risk factor for development of neuropsychiatric disorders such as major depressive disorder (MDD). In this review, we will discuss the regulation of autophagy in normal neurogenesis as well as during chronic psychological stress, focusing on the epigenetic control of autophagy in these contexts, and also highlight the lacunae in our understanding of this process. The systematic study of these regulatory mechanisms will provide a novel therapeutic strategy, based on the use epigenetic regulators of autophagy to enhance neurogenesis and potentially alleviate stress‐related behavioral disorders.

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Section: Epigenetic Control Of Autophagymentioning

confidence: 99%

Stress – (self) eating: Epigenetic regulation of autophagy in response to psychological stress

Puri

Subramanyam

2019

The FEBS Journal

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“…see Figure 1B). Examples for “silencing” histone modifications include histone 3 lysine 9 di-methylation (H3K9me2), H3K9 tri-methylation (H3K9me3), or H3K27me3, whereas histone 4 lysine 16 acetylation (H4K16ac), H3K4me3, H3K18ac, H3K27ac, or H3K56ac are markers of active transcription (10, 26–28).…”

Section: Introductionmentioning

confidence: 99%

The Role of Epigenetics in Autoimmune/Inflammatory Disease

2019

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Historically, systemic self-inflammatory conditions were classified as either autoinflammatory and caused by the innate immune system or autoimmune and driven by adaptive immune responses. However, it became clear that reality is much more complex and that autoimmune/inflammatory conditions range along an “inflammatory spectrum” with primarily autoinflammatory vs. autoimmune conditions resembling extremes at either end. Epigenetic modifications influence gene expression and alter cellular functions without modifying the genomic sequence. Methylation of CpG DNA dinucleotides and/or their hydroxymethylation, post-translational modifications to amino termini of histone proteins, and non-coding RNA expression are main epigenetic events. The pathophysiology of autoimmune/inflammatory diseases has been closely linked with disease causing gene mutations (rare) or a combination of genetic susceptibility and epigenetic modifications arising from exposure to the environment (more common). Over recent years, progress has been made in understanding molecular mechanisms involved in systemic inflammation and the contribution of innate and adaptive immune responses. Epigenetic events have been identified as (i) central pathophysiological factors in addition to genetic disease predisposition and (ii) as co-factors determining clinical pictures and outcomes in individuals with monogenic disease. Thus, a complete understanding of epigenetic contributors to autoimmune/inflammatory disease will result in approaches to predict individual disease outcomes and the introduction of effective, target-directed, and tolerable therapies. Here, we summarize recent findings that signify the importance of epigenetic modifications in autoimmune/inflammatory disorders along the inflammatory spectrum choosing three examples: the autoinflammatory bone condition chronic nonbacterial osteomyelitis (CNO), the “mixed pattern” disorder psoriasis, and the autoimmune disease systemic lupus erythematosus (SLE).

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“…Taken together our data suggest ERK1/2 activation regulates multiple components of autophagolysosome formation. A direct connection between ERK1/2 activation with autophagosome-lysosome fusion regulators has yet not been elucidated, but indirect connection through EGR1 or miR-138 holds the probable mechanisms 52 .…”

Section: Discussionmentioning

confidence: 99%

Molecular imaging of the kinetics of hyperactivated ERK1/2-mediated autophagy during acquirement of chemoresistance

et al. 2021

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Alterations in key kinases and signaling pathways can fine-tune autophagic flux to promote the development of chemoresistance. Despite empirical evidences of strong association between enhanced autophagic flux with acquired chemoresistance, it is still not understood whether an ongoing autophagic flux is required for both initiation, as well as maintenance of chemoresistance, or is sufficient for one of the either steps. Utilizing indigenously developed cisplatin–paclitaxel-resistant models of ovarian cancer cells, we report an intriguing oscillation in chemotherapy-induced autophagic flux across stages of resistance, which was found to be specifically elevated at the early stages or onset of chemoresistance. Conversely, the sensitive cells and cells at late stages of resistance showed stalled and reduced autophagic flux. This increased flux at early stages of resistance was found to be dictated by a hyperactive ERK1/2 signaling, which when inhibited either pharmacologically (U0126/Trametinib) or genetically, reduced p62 degradation, number of LC3+veLAMP1+ve puncta, autophagolysosome formation, and led to chemo-sensitization and apoptosis. Inhibition of ERK1/2 activation also altered the level of UVRAG and Rab7, the two key proteins involved in autophagosome–lysosome fusion. Noninvasive imaging of autophagic flux using a novel autophagy sensor (mtFL-p62 fusion reporter) showed that combinatorial treatment of platinum–taxol along with Trametinib/chloroquine blocked autophagic flux in live cells and tumor xenografts. Interestingly, Trametinib was found to be equally effective in blocking autophagic flux as chloroquine both in live cells and tumor xenografts. Combinatorial treatment of Trametinib and platinum–taxol significantly reduced tumor growth. This is probably the first report of real-time monitoring of chemotherapy-induced autophagy kinetics through noninvasive bioluminescence imaging in preclinical mouse model. Altogether our data suggest that an activated ERK1/2 supports proper completion of autophagic flux at the onset of chemoresistance to endure initial chemotherapeutic insult and foster the development of a highly chemoresistant phenotype, where autophagy becomes dispensable.

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Transcriptional and epigenetic profiling of nutrient-deprived cells to identify novel regulators of autophagy

Cited by 36 publications

References 60 publications

Stress – (self) eating: Epigenetic regulation of autophagy in response to psychological stress

Stress – (self) eating: Epigenetic regulation of autophagy in response to psychological stress

The Role of Epigenetics in Autoimmune/Inflammatory Disease

Molecular imaging of the kinetics of hyperactivated ERK1/2-mediated autophagy during acquirement of chemoresistance

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