Advances and Opportunities in Epigenetic Chemical Biology

Beyer, Jenna N.; Raniszewski, Nicole R.; Burslem, George M.

doi:10.1002/cbic.202000459

Cited by 10 publications

(12 citation statements)

References 422 publications

(625 reference statements)

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“…CpG methylation at these sites on promoters has been associated with gene silencing [ 28 – 30 ]. The CpG methylation events are carried out by DNA methyltransferases (DNMTs) or by the ten-eleven translocation family (TET) [ 31 – 33 ] ( Figure 6 ). In particular, DNMT1, DNMT3A, DNMT3B, TET1, TET2, and TET3 have been shown to be associated with the pathological transcriptional deregulation in many diseases [ 27 ].…”

Section: Applications Of Lcm To Epigenetic Studiesmentioning

confidence: 99%

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Laser Capture Microdissection in the Spatial Analysis of Epigenetic Modifications in Skin: A Comprehensive Review

Bhamidipati

Sinha

Sen

et al. 2022

Oxidative Medicine and Cellular Longevity

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Each cell in the body contains an intricate regulation for the expression of its relevant DNA. While every cell in a multicellular organism contains identical DNA, each tissue-specific cell expresses a different set of active genes. This organizational property exists in a paradigm that is largely controlled by forces external to the DNA sequence via epigenetic regulation. DNA methylation and chromatin modifications represent some of the classical epigenetic modifications that control gene expression. Complex tissues like skin consist of heterogeneous cell types that are spatially distributed and mixed. Furthermore, each individual skin cell has a unique response to physiological and pathological cues. As such, it is difficult to classify skin tissue as homogenous across all cell types and across different environmental exposures. Therefore, it would be prudent to isolate targeted tissue elements prior to any molecular analysis to avoid a possibility of confounding the sample with unwanted cell types. Laser capture microdissection (LCM) is a powerful technique used to isolate a targeted cell group with extreme microscopic precision. LCM presents itself as a solution to tackling the problem of tissue heterogeneity in molecular analysis. This review will cover an overview of LCM technology, the principals surrounding its application, and benefits of its application to the newly defined field of epigenomics, in particular of cutaneous pathology. This presents a comprehensive review about LCM and its use in the spatial analysis of skin epigenetics. Within the realm of skin pathology, this ability to isolate tissues under specific environmental stresses, such as oxidative stress, allows a far more focused investigation.

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Section: Applications Of Lcm To Epigenetic Studiesmentioning

confidence: 99%

“…Reproduced with permission from John Wiley and sons. The following original report was credited: Beyer et al [ 33 ].…”

Section: Figurementioning

confidence: 99%

Laser Capture Microdissection in the Spatial Analysis of Epigenetic Modifications in Skin: A Comprehensive Review

Bhamidipati

Sinha

Sen

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Both opposing chromatin-modifying enzymes additionally target non-histone proteins, e.g. tubulin in case of HDAC6 and SMC3 in case of HDAC8 [1][2][3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

Darwish

Ghazy

Heimburg

et al. 2022

Preprint

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While histone deacetylases (HDACs) are known as modulators of epigenetic gene regulation, they also control the activity of non-histone protein substrates. The isozyme HDAC8 plays a role in inhibiting apoptosis and increasing cancer cell proliferation. As a result, HDAC8 is considered a potential target in the treatment of cancer forms such as T-cell lymphoma, gastric adenocarcinoma, hepatocellular carcinoma, and childhood neuroblastoma. The present work describes the development of proteolysis targeting chimera (PROTAC) of HDAC8 based on substituted benzhydroxamic acids previously reported as potent and selective HDAC8 inhibitors. Within this study, we have developed the first in class HDAC8 selective PROTAC and investigated the effect on protein degradation and on the proliferation of neuroblastoma cells. The combination of structure-guided synthesis, in vitro screening and cellular testing resulted in cereblon (CRBN) based HDAC8 PROTACs that showed anti-neuroblastoma activity in cells.

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“…4,5 For example, acetylation of lysine residues on histone tails causes a reduction of positive charge at the nucleosome and a partial relaxation of chromatin, allowing access to transcriptionally active complexes. 2 There are a multitude of different post-translational modifications (PTMs) that are found at histone tails including acetylation, methylation, phosphorylation, and ubiquitination. 4 Often, multiple modifications and PTM crosstalk are required for levels of gene expression to be altered.…”

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confidence: 99%

“…2 Lysine PTMs are edited by a suite of reader, writer, and eraser proteins and regulate important cellular processes via the control of the chromatin state and therefore gene expression. 2,13 Modulation of lysine PTMs and their regulatory functions offers a unique opportunity for the discovery of new therapeutics, but selective inhibitors have yet to be identified for many targets or even protein classes. For example, attempts to discover inhibitors of lysine acetyltransferases (KATs) have been impeded by the frequent identification of molecules that cause pan-assay interference 14 or that exhibit poor selectivity.…”

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confidence: 99%

Focused Libraries for Epigenetic Drug Discovery: The Importance of Isosteres

Green

Burslem

2021

J. Med. Chem.

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Epigenetic drug discovery provides a wealth of opportunities for the discovery of new therapeutics but has been hampered by low hit rates, frequent identification of false-positives, and poor synthetic tractability. A key reason for this is that few screening collections consider the unique requirements of epigenetic targets despite significant medicinal chemistry interest.Here we analyze the suitability of some commercially available screening collections in the context of epigenetic drug discovery, with a particular focus on lysine post-translational modifications, and show that even privileged motifs found in U.S. Food and Drug Administration (FDA)-approved drugs are not present in these collections. We propose that the incorporation of epigenetic bioisosteres should become central in the design of new focused screening collections and highlight some opportunities for the development of synthetic methods which may improve the tractability of hit molecules.

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Advances and Opportunities in Epigenetic Chemical Biology

Cited by 10 publications

References 422 publications

Laser Capture Microdissection in the Spatial Analysis of Epigenetic Modifications in Skin: A Comprehensive Review

Laser Capture Microdissection in the Spatial Analysis of Epigenetic Modifications in Skin: A Comprehensive Review

Design, Synthesis and Biological Characterization of Histone Deacetylase 8 (HDAC8) Proteolysis Targeting Chimeras (PROTACs) with Anti-Neuroblastoma Activity

Focused Libraries for Epigenetic Drug Discovery: The Importance of Isosteres

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