bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒07‒24
six papers selected by
Ankita Daiya
BITS Pilani

  1. Methods Mol Biol. 2022 ;2535 171-185
      The transcription of each gene is tightly regulated by elements like promoters, enhancers, silencers and insulators. These elements determine the temporal and tissue-specific expression in development and disease. Drug resistance is the major obstacle in successfully treating cancer patients. In the recent years, it became evident that epigenetic changes represent one of the mechanisms that contribute to the onset and progression of cancer but also to the development of therapy resistance. The assay for transposase-accessible chromatin coupled with next generation sequencing (ATAC-seq) is a fast and easy technique to track epigenetic changes that result in different opening of the chromatin in regulatory regions genome-wide. The transposase cuts DNA in regions that are open and therefore accessible for transcription factors, regulatory RNAs and proteins that alter the architectural structure of the DNA and drive or inhibit transcription through the RNA polymerase. Here we describe a detailed protocol to perform an ATAC-seq of cells from culture or tissue.
    Keywords:  ATAC-seq; Chromatin; Cis-acting elements; Enhancer; Epigenome; Epigenomic; Insulator; Promoter; Silencer; Transcription factors
  2. Curr Opin Plant Biol. 2022 Jul 13. pii: S1369-5266(22)00090-5. [Epub ahead of print]69 102261
      Chromatin organization is important for many DNA-templated processes in eukaryotic cells such as replication and transcription. Recent studies have uncovered the capacity of epigenetic modifications, phase separation, and nuclear architecture and spatial positioning to regulate chromatin organization in both plants and animals. Here, we provide an overview of the recent progress made in understanding how chromatin is organized within the nucleus at both the local and global levels with respect to the regulation of transcriptional silencing in plants. To be concise while covering important mechanisms across a range of scales, we focus on how epigenetic modifications and chromatin remodelers alter local chromatin structure, how liquid-liquid phase separation physically separates broader chromatin domains into distinct droplets, and how nuclear positioning affects global chromatin organization.
    Keywords:  Chromatin organization; Epigenetic modifications; Transcriptional regulation
  3. Mol Syst Biol. 2022 Jul;18(7): e11168
      Similar to persister bacterial cells that survive antibiotic treatments, some cancer cells can evade drug treatments. This Commentary discusses the different classes of persister cells and their implications for developing more efficient cancer treatments.
  4. Nat Commun. 2022 Jul 20. 13(1): 4199
      The genome can be divided into two spatially segregated compartments, A and B, which partition active and inactive chromatin states. While constitutive heterochromatin is predominantly located within the B compartment near the nuclear lamina, facultative heterochromatin marked by H3K27me3 spans both compartments. How epigenetic modifications, compartmentalization, and lamina association collectively maintain heterochromatin architecture remains unclear. Here we develop Lamina-Inducible Methylation and Hi-C (LIMe-Hi-C) to jointly measure chromosome conformation, DNA methylation, and lamina positioning. Through LIMe-Hi-C, we identify topologically distinct sub-compartments with high levels of H3K27me3 and differing degrees of lamina association. Inhibition of Polycomb repressive complex 2 (PRC2) reveals that H3K27me3 is essential for sub-compartment segregation. Unexpectedly, PRC2 inhibition promotes lamina association and constitutive heterochromatin spreading into H3K27me3-marked B sub-compartment regions. Consistent with this repositioning, genes originally marked with H3K27me3 in the B compartment, but not the A compartment, remain largely repressed, suggesting that constitutive heterochromatin spreading can compensate for H3K27me3 loss at a transcriptional level. These findings demonstrate that Polycomb sub-compartments and their antagonism with lamina association are fundamental features of genome structure. More broadly, by jointly measuring nuclear position and Hi-C contacts, our study demonstrates how compartmentalization and lamina association represent distinct but interdependent modes of heterochromatin regulation.
  5. Exp Biol Med (Maywood). 2022 Jul 21. 15353702221110645
      As a major co-factor of F-actin depolymerization, WD-repeat domain 1 (WDR1) affects the cellular microenvironment by cytoskeleton remodeling, thereby influencing cell molecular behavior. Our previous study showed that WDR1 activates YAP (Yes-associated protein) signaling in non-small-cell lung cancer (NSCLC) cells, but the mechanism remains unclear. We discovered that knockdown WDR1 in NSCLC cells decreased the expression of YAP and the nucleus-to-cytoplasm ratio. Disruption of cortical stress by drugs significantly inhibited YAP nuclear trafficking and enhanced YAP phosphorylation. In WDR1-knockdown NSCLC cells, inhibition of Hippo pathway reduced the nuclear exclusion of YAP and phosphorylated YAP. Our data suggest that WDR1-mediated cortical stress might be involved in regulating YAP signaling, thereby affecting the proliferation and migration of NSCLC cells.
    Keywords:  WDR1; YAP; cytoskeleton; non-small-cell lung cancer
  6. Int J Biol Sci. 2022 ;18(11): 4497-4512
      YAP (gene symbol YAP1) as a potential oncoprotein, is positively correlated with the malignancy of various tumors. However, overexpression of YAP alone in multiple normal tissue cells has failed to induce tumor formation and the underlying mechanism is poorly understood. Herein, we show that YAP activation directly induces transcription of its negative regulator, SAV1, to constitute a negative feedback loop, which plays a vital role in maintaining lung epithelial cell homeostasis and was dysregulated in non-small cell lung cancer (NSCLC). Notably, smoking promotes the hypermethylation of the SAV1 promoter region, which disrupts YAP negative feedback by inactivating the Hippo pathway. Besides, exogenous overexpression of SAV1 can act as a traffic protein, activating the Hippo signaling and concurrently inhibiting the WNT pathway to decrease cancer cell growth. Furthermore, using the lung cancer organoids, we found that lentivirus-mediated SAV1 gene transfer combined with methylation inhibitor and YAP-TEAD inhibitor is a potential feasible clinical medication regimen for the lung cancer patient, especially among the smoking population. Thus, this SAV1 mediated feedback loop provides an efficient mechanism to establish the robustness and homeostasis of YAP regulation and as a potential target of gene therapy for the smoking NSCLC population.
    Keywords:  Lung Cancer; Methylation; SAV1; Tobacco smoking; YAP