bims-ectoca 2023-07-02 papers

Ann N Y Acad Sci. 2023 Jun 30.

Inheritance of epigenetic transcriptional memory through read-write replication of a histone modification.

Epigenetic transcriptional regulation frequently requires histone modifications. Some, but not all, of these modifications are able to template their own inheritance. Here, I discuss the molecular mechanisms by which histone modifications can be inherited and relate these ideas to new results about epigenetic transcriptional memory, a phenomenon that poises recently repressed genes for faster reactivation and has been observed in diverse organisms. Recently, we found that the histone H3 lysine 4 dimethylation that is associated with this phenomenon plays a critical role in sustaining memory and, when factors critical for the establishment of memory are inactivated, can be stably maintained through multiple mitoses. This chromatin-mediated inheritance mechanism may involve a physical interaction between an H3K4me2 reader, SET3C, and an H3K4me2 writer, Spp1- COMPASS. This is the first example of a chromatin-mediated inheritance of a mark that promotes transcription.

Keywords: chromatin; epigenetics; memory; transcription

DOI: https://doi.org/10.1111/nyas.15033

Cancer Metastasis Rev. 2023 Jun 28.

Cancer metastasis under the magnifying glass of epigenetics and epitranscriptomics.

Maxime Janin, Veronica Davalos, Manel Esteller.

Most of the cancer-associated mortality and morbidity can be attributed to metastasis. The role of epigenetic and epitranscriptomic alterations in cancer origin and progression has been extensively demonstrated during the last years. Both regulations share similar mechanisms driven by DNA or RNA modifiers, namely writers, readers, and erasers; enzymes responsible of respectively introducing, recognizing, or removing the epigenetic or epitranscriptomic modifications. Epigenetic regulation is achieved by DNA methylation, histone modifications, non-coding RNAs, chromatin accessibility, and enhancer reprogramming. In parallel, regulation at RNA level, named epitranscriptomic, is driven by a wide diversity of chemical modifications in mostly all RNA molecules. These two-layer regulatory mechanisms are finely controlled in normal tissue, and dysregulations are associated with every hallmark of human cancer. In this review, we provide an overview of the current state of knowledge regarding epigenetic and epitranscriptomic alterations governing tumor metastasis, and compare pathways regulated at DNA or RNA levels to shed light on a possible epi-crosstalk in cancer metastasis. A deeper understanding on these mechanisms could have important clinical implications for the prevention of advanced malignancies and the management of the disseminated diseases. Additionally, as these epi-alterations can potentially be reversed by small molecules or inhibitors against epi-modifiers, novel therapeutic alternatives could be envisioned.

Keywords: Cancer metastasis; Cancer treatment; Epigenetic; Epitranscriptomic

DOI: https://doi.org/10.1007/s10555-023-10120-3

J Cell Biol. 2023 Sep 04. pii: e202209120. [Epub ahead of print]222(9):

Mechanical control of the mammalian circadian clock via YAP/TAZ and TEAD.

Juan F Abenza, Leone Rossetti, Malèke Mouelhi, Javier Burgués, Ion Andreu, Keith Kennedy, Pere Roca-Cusachs, Santiago Marco, Jordi García-Ojalvo, Xavier Trepat.

Autonomous circadian clocks exist in nearly every mammalian cell type. These cellular clocks are subjected to a multilayered regulation sensitive to the mechanochemical cell microenvironment. Whereas the biochemical signaling that controls the cellular circadian clock is increasingly well understood, mechanisms underlying regulation by mechanical cues are largely unknown. Here we show that the fibroblast circadian clock is mechanically regulated through YAP/TAZ nuclear levels. We use high-throughput analysis of single-cell circadian rhythms and apply controlled mechanical, biochemical, and genetic perturbations to study the expression of the clock gene Rev-erbα. We observe that Rev-erbα circadian oscillations are disrupted with YAP/TAZ nuclear translocation. By targeted mutations and overexpression of YAP/TAZ, we show that this mechanobiological regulation, which also impacts core components of the clock such as Bmal1 and Cry1, depends on the binding of YAP/TAZ to the transcriptional effector TEAD. This mechanism could explain the impairment of circadian rhythms observed when YAP/TAZ activity is upregulated, as in cancer and aging.

DOI: https://doi.org/10.1083/jcb.202209120

Am J Physiol Gastrointest Liver Physiol. 2023 Jun 27.

Lipophilic statins inhibit YAP co-activator transcriptional activity in HCC cells through Rho-mediated modulation of the actin cytoskeleton.

Jihane N Benhammou, Bo Qiao, Arthur Ko, James Sinnett-Smith, Joseph Pisegna, Enrique Rozengurt.

Introduction: Hepatocellular carcinoma (HCC) is the third leading cause of liver-related death. Lipophilic statins have been associated with a decrease in HCC incidence, raising the possibility of their use as chemoprevention agents. The Yes associated protein (YAP) and Transcriptional co-Activator (TAZ) have emerged as an important pro-oncogenic mechanism in HCC. Statins modulate YAP/TAZ in other solid tumors but few studies have assessed their mechanisms in HCC. We aimed to delineate how lipophilic statins regulate YAP protein localization by interrogating the mevalonate pathway in a step-wise fashion using pharmacological and genetic approaches in HCC cells. Methods: Huh7 and Hep3B HCC cells were treated with the lipophilic statins cerivastatin and atorvastatin. YAP protein localization was determined using quantitative immunofluorescence (IF) imaging. The gene expression of CTGF and CYR61, known YAP/TEAD-regulated genes, were measured using quantitative real-time PCR. Rescue experiments were conducted using metabolites of the mevalonate pathway including mevalonic acid and geranylgeranyl pyrophosphate (GG-PP). The cellular cytoskeleton was assessed using F-actin IF staining. Results: YAP protein was extruded from the nucleus to the cytoplasm with statin treatment. Consistently, CTGF and CYR61 mRNA expression significantly decreased with statins. Cytoskeletal structure was also compromised with statins. Gene expression, YAP protein localization and cytoskeletal structure were all restored to baseline with exogenous GG-PP but not with other metabolites of the mevalonate pathway. Direct Rho GTPase inhibitor treatment mirrored the statin effects on YAP. Conclusions: YAP protein localization is regulated by lipophilic statins via Rho GTPases causing cytoskeletal structural changes and is independent of cholesterol metabolites.

Keywords: Statins; YAP; chemoprevention; hepatocellular carcinoma

DOI: https://doi.org/10.1152/ajpgi.00089.2023