bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒12‒10
six papers selected by
Ankita Daiya, BITS Pilani
  1. Histone deacetylase 6: at the interface of cancer and neurodegeneration.
  2. ChromaFactor: deconvolution of single-molecule chromatin organization with non-negative matrix factorization.
  3. EP300 promotes lung cancer cell proliferation by regulating the oncogenic transcription of Hippo-YAP signaling pathway.
  4. YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration.
  5. JMnorm: a novel joint multi-feature normalization method for integrative and comparative epigenomics.
  6. Distinct Histone H3 Lysine 27 Modifications Dictate Different Outcomes of Gene Transcription.
  1. Epigenomics. 2023 Dec 07.
    Histone deacetylase 6: at the interface of cancer and neurodegeneration.
    Jingjing Pu, Amit Sharma, Jian Hou, Ingo Gh Schmidt-Wolf.
      With the recognition in the early 1960s that histones can be post-translationally modified, the list of different post-translational modifications of histones and their biological consequences has continued to expand. In addition, the idea of the 'histone code' hypothesis, later introduced by David Allis and colleagues, further broaden the horizon of chromatin biology. Currently, there is a wealth of knowledge about the transition between the active and the repressive state of chromatin, and modifications of histones remains at the center of chromatin biology. Histone deacetylases (HDACs) in particular are of great importance for the therapeutic success of cancer treatment. Focusing primarily on HDAC6, herein we have briefly highlighted its unique involvement in cancer and also apparently in neurodegeneration.
    Keywords:  cancer; epigenetics; histone deacetylase; neurodegeneration; therapy
    DOI:  https://doi.org/10.2217/epi-2023-0373
  2. bioRxiv. 2023 Nov 22. pii: 2023.11.22.568268. [Epub ahead of print]
    ChromaFactor: deconvolution of single-molecule chromatin organization with non-negative matrix factorization.
    Laura M Gunsalus, Michael J Keiser, Katherine S Pollard.
      The investigation of chromatin organization in single cells holds great promise for identifying causal relationships between genome structure and function. However, analysis of single-molecule data is hampered by extreme yet inherent heterogeneity, making it challenging to determine the contributions of individual chromatin fibers to bulk trends. To address this challenge, we propose ChromaFactor, a novel computational approach based on non-negative matrix factorization that deconvolves single-molecule chromatin organization datasets into their most salient primary components. ChromaFactor provides the ability to identify trends accounting for the maximum variance in the dataset while simultaneously describing the contribution of individual molecules to each component. Applying our approach to two single-molecule imaging datasets across different genomic scales, we find that these primary components demonstrate significant correlation with key functional phenotypes, including active transcription, enhancer-promoter distance, and genomic compartment. ChromaFactor offers a robust tool for understanding the complex interplay between chromatin structure and function on individual DNA molecules, pinpointing which subpopulations drive functional changes and fostering new insights into cellular heterogeneity and its implications for bulk genomic phenomena.
    DOI:  https://doi.org/10.1101/2023.11.22.568268
  3. Biochem Biophys Res Commun. 2023 Nov 28. pii: S0006-291X(23)01424-9. [Epub ahead of print]692 149330
    EP300 promotes lung cancer cell proliferation by regulating the oncogenic transcription of Hippo-YAP signaling pathway.
    Shasha Li, Jing Shi, Lulu Wang, Danru Zhang, Huixia Zhang.
      The transcriptional activation function of YAP in cancer development has been widely studied. However, the underlying regulatory mechanisms remain largely unknown. In this study, we found that EP300, one histone acetyltransferase, interacted with YAP and was recruited into the phase separated condensates of YAP. Transcriptomic analysis revealed substantial alterations in gene expression upon EP300 depletion, with downregulated genes associated with cancer progression and Hippo-YAP pathway. Notably, disruption of EP300 inhibited the transcriptional activation of YAP and reduced the binding of H3K27ac on YAP target oncogenes in Hippo pathway. Moreover, depletion of EP300 effectively inhibited YAP-driven tumor growth. Taken together, these results indicate that EP300 contributes to lung cancer progression by promoting the oncogenic transcription of YAP through H3K27ac, which suggests that YAP-EP300 axis may be potential therapeutic targets for lung cancer treatment.
    Keywords:  EP300; Hippo pathway; Lung cancer; Oncogenic transcription; YAP
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149330
  4. Cell Rep. 2023 Nov 30. pii: S2211-1247(23)01509-7. [Epub ahead of print]42(12): 113497
    YAP targetome reveals activation of SPEM in gastric pre-neoplastic progression and regeneration.
    Adrian K H Loe, Abilasha Rao-Bhatia, Zhao Wei, Jung-Eun Kim, Bingxin Guan, Yan Qin, Minji Hong, Hyo Sang Kwak, Xiaoyu Liu, Leyi Zhang, Jeffrey L Wrana, Haiyang Guo, Tae-Hee Kim.
      Peptic ulcer disease caused by environmental factors increases the risk of developing gastric cancer (GC), one of the most common and deadly cancers in the world. However, the mechanisms underlying this association remain unclear. A major type of GC uniquely undergoes spasmolytic polypeptide-expressing metaplasia (SPEM) followed by intestinal metaplasia. Notably, intestinal-type GC patients with high levels of YAP signaling exhibit a lower survival rate and poor prognosis. YAP overexpression in gastric cells induces atrophy, metaplasia, and hyperproliferation, while its deletion in a Notch-activated gastric adenoma model suppresses them. By defining the YAP targetome genome-wide, we demonstrate that YAP binds to active chromatin elements of SPEM-related genes, which correlates with the activation of their expression in both metaplasia and ulcers. Single-cell analysis combined with our YAP signature reveals that YAP signaling is activated during SPEM, demonstrating YAP as a central regulator of SPEM in gastric neoplasia and regeneration.
    Keywords:  CP: Stem cell research; HIPPO pathway; YAP signaling; gastric cancer; metaplasia; peptic ulcer; regeneration
    DOI:  https://doi.org/10.1016/j.celrep.2023.113497
  5. Nucleic Acids Res. 2023 Dec 06. pii: gkad1146. [Epub ahead of print]
    JMnorm: a novel joint multi-feature normalization method for integrative and comparative epigenomics.
    Guanjue Xiang, Yuchun Guo, David Bumcrot, Alla Sigova.
      Combinatorial patterns of epigenetic features reflect transcriptional states and functions of genomic regions. While many epigenetic features have correlated relationships, most existing data normalization approaches analyze each feature independently. Such strategies may distort relationships between functionally correlated epigenetic features and hinder biological interpretation. We present a novel approach named JMnorm that simultaneously normalizes multiple epigenetic features across cell types, species, and experimental conditions by leveraging information from partially correlated epigenetic features. We demonstrate that JMnorm-normalized data can better preserve cross-epigenetic-feature correlations across different cell types and enhance consistency between biological replicates than data normalized by other methods. Additionally, we show that JMnorm-normalized data can consistently improve the performance of various downstream analyses, which include candidate cis-regulatory element clustering, cross-cell-type gene expression prediction, detection of transcription factor binding and changes upon perturbations. These findings suggest that JMnorm effectively minimizes technical noise while preserving true biologically significant relationships between epigenetic datasets. We anticipate that JMnorm will enhance integrative and comparative epigenomics.
    DOI:  https://doi.org/10.1093/nar/gkad1146
  6. J Mol Biol. 2023 Dec 04. pii: S0022-2836(23)00487-4. [Epub ahead of print] 168376
    Distinct Histone H3 Lysine 27 Modifications Dictate Different Outcomes of Gene Transcription.
    Tsuyoshi Konuma, Ming-Ming Zhou.
      Site-specific histone modifications have long been recognized to play an important role in directing gene transcription in chromatin in biology of health and disease. However, concrete illustration of how different histone modifications in a site-specific manner dictate gene transcription outcomes, as postulated in the influential "Histone code hypothesis", introduced by Allis and colleagues in 2000, has been lacking. In this review, we summarize our latest understanding of the dynamic regulation of gene transcriptional activation, silence, and repression in chromatin that is directed distinctively by histone H3 lysine 27 acetylation, methylation, and crotonylation, respectively. This represents a specific example of a long-anticipated verification of the "Histone code hypothesis."
    DOI:  https://doi.org/10.1016/j.jmb.2023.168376
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