bims-ectoca 2021-11-14 papers

Issue of 2021‒11‒14
seven papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Int J Mol Sci. 2021 Oct 30. pii: 11810. [Epub ahead of print]22(21):

Deacetylation of Transcription Factors in Carcinogenesis.

Marta Halasa, Kamila Adamczuk, Grzegorz Adamczuk, Syeda Afshan, Andrzej Stepulak, Marek Cybulski, Anna Wawruszak.

Reversible Nε-lysine acetylation/deacetylation is one of the most common post-translational modifications (PTM) of histones and non-histone proteins that is regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs). This epigenetic process is highly involved in carcinogenesis, affecting histone and non-histone proteins' properties and their biological functions. Some of the transcription factors, including tumor suppressors and oncoproteins, undergo this modification altering different cell signaling pathways. HDACs deacetylate their targets, which leads to either the upregulation or downregulation of proteins involved in the regulation of cell cycle and apoptosis, ultimately influencing tumor growth, invasion, and drug resistance. Therefore, epigenetic modifications are of great clinical importance and may constitute a new therapeutic target in cancer treatment. This review is aimed to present the significance of HDACs in carcinogenesis through their influence on functions of transcription factors, and therefore regulation of different signaling pathways, cancer progression, and metastasis.

Keywords: HDAC; histone deacetylase inhibitors (HDIs); transcription factors

DOI: https://doi.org/10.3390/ijms222111810

Biochem Soc Trans. 2021 Nov 08. pii: BST20210450. [Epub ahead of print]

Structural insights into the interactions of Polycomb Repressive Complex 2 with chromatin.

Akhil Gargey Iragavarapu, Liqi Yao, Vignesh Kasinath.

Polycomb repressive complexes are a family of chromatin modifier enzymes which are critical for regulating gene expression and maintaining cell-type identity. The reversible chemical modifications of histone H3 and H2A by the Polycomb proteins are central to its ability to function as a gene silencer. PRC2 is both a reader and writer of the tri-methylation of histone H3 lysine 27 (H3K27me3) which serves as a marker for transcription repression, and heterochromatin boundaries. Over the last few years, several studies have provided key insights into the mechanisms regulating the recruitment and activation of PRC2 at Polycomb target genes. In this review, we highlight the recent structural studies which have elucidated the roles played by Polycomb cofactor proteins in mediating crosstalk between histone post-translational modifications and the recruitment of PRC2 and the stimulation of PRC2 methyltransferase activity.

Keywords: chromatin; cryo-electron microscopy; epigenetics; eukaryotic gene expression; transcription

DOI: https://doi.org/10.1042/BST20210450

Semin Cell Dev Biol. 2021 Nov 08. pii: S1084-9521(21)00264-0. [Epub ahead of print]

An emergent Wnt5a/YAP/TAZ regulatory circuit and its possible role in cancer.

Pablo Astudillo.

Wnt5a is a ligand that plays several roles in development, homeostasis, and disease. A growing body of evidence indicates that Wnt5a is involved in cancer progression. Despite extensive research in this field, our knowledge about how Wnt5a is precisely involved in cancer is still incomplete. It is usually thought that certain combinations of Frizzled receptors and co-receptors might explain the observed effects of Wnt5a either as a tumor suppressor or by promoting migration and invasion. While accepting this 'receptor context' model, this review proposes that Wnt5a is integrated within a larger regulatory circuit involving β-catenin, YAP/TAZ, and LATS1/2. Remarkably, WNT5A and YAP1 are transcriptionally regulated by the Hippo and Wnt pathways, respectively, and might form a regulatory circuit acting through LATS kinases and secreted Wnt/β-catenin inhibitors, including Wnt5a itself. Therefore, understanding the precise role of Wnt5a and YAP in cancer requires a systems biology perspective.

Keywords: Cancer; EMT; Regulatory networks; TAZ; Wnt5a; YAP; β-catenin

DOI: https://doi.org/10.1016/j.semcdb.2021.10.001

Open Biol. 2021 Nov;11(11): 210256

Mechanotransduction as a major driver of cell behaviour: mechanisms, and relevance to cell organization and future research.

Pierre-Henri Puech, Pierre Bongrand.

How do cells process environmental cues to make decisions? This simple question is still generating much experimental and theoretical work, at the border of physics, chemistry and biology, with strong implications in medicine. The purpose of mechanobiology is to understand how biochemical and physical cues are turned into signals through mechanotransduction. Here, we review recent evidence showing that (i) mechanotransduction plays a major role in triggering signalling cascades following cell-neighbourhood interaction; (ii) the cell capacity to continually generate forces, and biomolecule properties to undergo conformational changes in response to piconewton forces, provide a molecular basis for understanding mechanotransduction; and (iii) mechanotransduction shapes the guidance cues retrieved by living cells and the information flow they generate. This includes the temporal and spatial properties of intracellular signalling cascades. In conclusion, it is suggested that the described concepts may provide guidelines to define experimentally accessible parameters to describe cell structure and dynamics, as a prerequisite to take advantage of recent progress in high-throughput data gathering, computer simulation and artificial intelligence, in order to build a workable, hopefully predictive, account of cell signalling networks.

Keywords: T lymphocyte activation; biomolecular interactions; catch bonds; cytoskeleton; mechanics; signalling

DOI: https://doi.org/10.1098/rsob.210256

Cell Mol Biol Lett. 2021 Nov 10. 26(1): 45

The low-complexity domains of the KMT2D protein regulate histone monomethylation transcription to facilitate pancreatic cancer progression.

Weihan Li, Lei Wu, Hui Jia, Zenghua Lin, Renhao Zhong, Yukun Li, Chenwei Jiang, Shifan Liu, Xiaorong Zhou, Erhao Zhang.

BACKGROUND: Liquid-liquid phase separation (LLPS) within the nucleus is directly linked to driving gene expression through transcriptional complexes. Histone lysine methyltransferase 2D (KMT2D) is widely present in many cancers. It is known to epigenetically stimulate the expression of genes associated with tumorigenesis and metastasis. Our analyses show that KMT2D possesses two distinct low-complexity domains (LCDs) capable of driving the assembly of membrane-less condensates. The dependence of the mechanisms underlying monomethylation of H3K4 on the LLPS microenvironment derived from KMT2D LCDs is unclear in tumor.METHODS: KMT2D LCD-depletion cells were used to investigate tumor cell proliferation, apoptosis, and migration. We identified some core proteins, including WDR5, RBBP5, and ASH2L, which are involved in the KMT2D-associated catalytic complex in KMT2D LCD-deficient cells to further elucidate the mechanism that decreases monomethylation of H3K4. We also evaluated the viability of KMT2D LCD-deficient cells in vivo. Finally, using 1,6-hexanediol (HD), an inhibitor of LLPS, we determined cell activities associated with KMT2D function in wild-type PANC-1 cells.
RESULTS: Without the LLPS microenvironment in KMT2D LCD-deficient cells or wild-type PANC-1 cells treated with HD, the WDR5 protein was significantly less stable and the protein-protein interactions between the components of the KMT2D-enzyme complex were attenuated, impairing the formation of the complex. Moreover, with the decrease in H3K4me1 level at enhancers, transcription factors such as LIFR and KLF4 were markedly downregulated, effectively inhibiting tumor progression. In xenograft tumor models, PANC-1 cells lacking the KMT2D LCDs showed effectively suppressed tumor growth compared to normal cells.
CONCLUSIONS: Our data indicate that the two low-complexity domains of the KMT2D protein could form a stable LLPS microenvironment, promoting the KMT2D catalysis of H3K4 monomethylation through stabilization of the WDR5 protein and KMT2D-enzyme complex. Therefore, finding ways to regulate the LLPS microenvironment will be benefitial for new cancer treatment strategies.

Keywords: Epigenetic therapy; H3K4 monomethylation; KMT2D; Liquid–liquid phase separation; Low-complexity domain

DOI: https://doi.org/10.1186/s11658-021-00292-7

Nucleic Acids Res. 2021 Nov 11. pii: gkab1032. [Epub ahead of print]

scEnhancer: a single-cell enhancer resource with annotation across hundreds of tissue/cell types in three species.

Tianshun Gao, Zilong Zheng, Yihang Pan, Chengming Zhu, Fuxin Wei, Jinqiu Yuan, Rui Sun, Shuo Fang, Nan Wang, Yang Zhou, Jiang Qian.

Previous studies on enhancers and their target genes were largely based on bulk samples that represent 'average' regulatory activities from a large population of millions of cells, masking the heterogeneity and important effects from the sub-populations. In recent years, single-cell sequencing technology has enabled the profiling of open chromatin accessibility at the single-cell level (scATAC-seq), which can be used to annotate the enhancers and promoters in specific cell types. A comprehensive resource is highly desirable for exploring how the enhancers regulate the target genes at the single-cell level. Hence, we designed a single-cell database scEnhancer (http://enhanceratlas.net/scenhancer/), covering 14 527 776 enhancers and 63 658 600 enhancer-gene interactions from 1 196 906 single cells across 775 tissue/cell types in three species. An unsupervised learning method was employed to sort and combine tens or hundreds of single cells in each tissue/cell type to obtain the consensus enhancers. In addition, we utilized a cis-regulatory network algorithm to identify the enhancer-gene connections. Finally, we provided a user-friendly platform with seven useful modules to search, visualize, and browse the enhancers/genes. This database will facilitate the research community towards a functional analysis of enhancers at the single-cell level.

DOI: https://doi.org/10.1093/nar/gkab1032

Molecules. 2021 Nov 05. pii: 6694. [Epub ahead of print]26(21):

Current Analytical Strategies in Studying Chromatin-Associated-Proteome (Chromatome).

Niamat Khan, Sidra Shahid, Abdul R Asif.

Chromatin is a dynamic structure comprising of DNA and proteins. Its unique nature not only help to pack the DNA tightly within the cell but also is pivotal in regulating gene expression DNA replication. Furthermore it also protects the DNA from being damaged. Various proteins are involved in making a specific complex within a chromatin and the knowledge about these interacting partners is helpful to enhance our understanding about the pathophysiology of various chromatin associated diseases. Moreover, it could also help us to identify new drug targets and design more effective remedies. Due to the existence of chromatin in different forms under various physiological conditions it is hard to develop a single strategy to study chromatin associated proteins under all conditions. In our current review, we tried to provide an overview and comparative analysis of the strategies currently adopted to capture the DNA bounded protein complexes and their mass spectrometric identification and quantification. Precise information about the protein partners and their function in the DNA-protein complexes is crucial to design new and more effective therapeutic molecules against chromatin associated diseases.

Keywords: PICh; QTIP; centromere; chromatin; chromatin immunoprecipitation (ChIP); euchromatin; heterochromatin; iTRAQ; interphase; proteome; telomere

DOI: https://doi.org/10.3390/molecules26216694