Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies DOI Creative Commons
Xiaopeng Peng, Zhihao Hu,

Limei Zeng

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(2), P. 533 - 578

Published: Sept. 12, 2023

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over past few decades, significant progress has been made development targeted epigenetic modulators (e.g., inhibitors). However, inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack subtype selectivity, drug resistance. As result, design new degraders) such as PROTACs, molecular glue, hydrophobic tagging (HyT) degraders garnered attention from both academia pharmaceutical industry, numerous discovered decade. In this review, we aim to provide an in-depth illustration degrading strategies (2017–2023) targeting proteins for cancer therapy, focusing on rational design, pharmacodynamics, pharmacokinetics, status, crystal structure information these degraders. Importantly, also deep insights into potential challenges corresponding remedies approach development. Overall, hope review will offer better mechanistic understanding serve useful guide emerging epigenetic-targeting

Language: Английский

Modulation of cellular processes by histone and non-histone protein acetylation DOI
Maria Shvedunova, Asifa Akhtar

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 23(5), P. 329 - 349

Published: Jan. 18, 2022

Language: Английский

Citations

541
Deciphering the multi-scale, quantitative cis-regulatory code DOI Creative Commons
Seungsoo Kim, Joanna Wysocka

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(3), P. 373 - 392

Published: Jan. 23, 2023

Uncovering the cis-regulatory code that governs when and how much each gene is transcribed in a given genome cellular state remains central goal of biology. Here, we discuss major layers regulation influence transcriptional outputs are encoded by DNA sequence context. We first transcription factors bind specific sequences dosage-dependent cooperative manner then proceed to cofactors facilitate factor function mediate activity modular elements such as enhancers, silencers, promoters. consider complex poorly understood interplay these diverse within regulatory landscapes its relationships with chromatin states nuclear organization. propose mechanistically informed, quantitative model integrates multiple will be key ultimately cracking code.

Language: Английский

Citations

178
Regulation, functions and transmission of bivalent chromatin during mammalian development DOI
Trisha A. Macrae, Julie Fothergill-Robinson, Miguel Ramalho‐Santos

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2022, Volume and Issue: 24(1), P. 6 - 26

Published: Aug. 26, 2022

Language: Английский

Citations

119
Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets DOI Creative Commons
Ruiqi Liu,

Jiajun Wu,

H. Henry Guo

et al.

MedComm, Journal Year: 2023, Volume and Issue: 4(3)

Published: May 20, 2023

Abstract Histones are DNA‐binding basic proteins found in chromosomes. After the histone translation, its amino tail undergoes various modifications, such as methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation, which together constitute “histone code.” The relationship between their combination biological function can be used an important epigenetic marker. Methylation demethylation of same residue, acetylation deacetylation, phosphorylation dephosphorylation, even methylation different residues cooperate or antagonize with each other, forming a complex network. Histone‐modifying enzymes, cause numerous codes, have become hot topic research on cancer therapeutic targets. Therefore, thorough understanding role post‐translational modifications (PTMs) cell life activities is very for preventing treating human diseases. In this review, several most thoroughly studied newly discovered PTMs introduced. Furthermore, we focus histone‐modifying enzymes carcinogenic potential, abnormal modification sites tumors, multiple essential molecular regulation mechanism. Finally, summarize missing areas current point out direction future research. We hope to provide comprehensive promote further field.

Language: Английский

Citations

114
Generating specificity in genome regulation through transcription factor sensitivity to chromatin DOI
Luke Isbel, Ralph S. Grand, Dirk Schübeler

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(12), P. 728 - 740

Published: July 12, 2022

Language: Английский

Citations

105
Prediction of histone post-translational modification patterns based on nascent transcription data DOI
Zhong Wang, Alexandra G. Chivu, Lauren A. Choate

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(3), P. 295 - 305

Published: March 1, 2022

Language: Английский

Citations

82
Epigenetic regulation of macrophage polarization in wound healing DOI Creative Commons
Cheng Chen, Tengfei Liu, Yuanyang Tang

et al.

Burns & Trauma, Journal Year: 2023, Volume and Issue: 11

Published: Jan. 1, 2023

The immune microenvironment plays a critical role in regulating skin wound healing. Macrophages, the main component of infiltrating inflammatory cells, play pivotal shaping process Macrophages comprise classic proinflammatory M1 subtype and anti-inflammatory M2 population. In early phase closure, M1-like macrophages initiate amplify local response to disinfect injured tissue. late tissue-repairing phase, are predominant tissue limit inflammation promote repair. biological function is tightly linked with epigenomic organization. Transcription factors essential for macrophage polarization. Epigenetic modification transcription determines heterogeneity macrophages. contrast, also regulate expression epigenetic enzymes. Both enzymes form complex network that regulates plasticity Here, we describe latest knowledge concerning potential mechanisms precisely their effects on

Language: Английский

Citations

48
Lactylation: novel epigenetic regulatory and therapeutic opportunities DOI

Haoqin Fan,

Fan Yang, Zhenghui Xiao

et al.

AJP Endocrinology and Metabolism, Journal Year: 2023, Volume and Issue: 324(4), P. E330 - E338

Published: March 1, 2023

Lactate, which is an end product of glycolysis, has traditionally been considered a metabolic waste. However, numerous studies have demonstrated that lactate serves and nonmetabolic functions in physiological processes multiple diseases. Cancer pulmonary arterial hypertension shown to undergo reprogramming, accompanied by increased production. Metabolic reprogramming epigenetic modifications extensively linked; furthermore, posttranslational histones caused metabolites play vital role alterations. In this paper, we reviewed recent research on lactate-induced histone provided new vision about the effect glycolysis. Based our review, cross talk between metabolome epigenome induced glycolysis may indicate novel regulatory therapeutic opportunities. There magnificent progress interaction metabolomics epigenomics decades, but many questions still remained be investigated. Lactylation found different pathophysiological states leads diverse biological effects; however, only few mechanisms lactylation illustrated. Further would provide us with better understanding epigenomics.

Language: Английский

Citations

47
Cell type–specific 3D-genome organization and transcription regulation in the brain DOI Creative Commons

Shiwei Liu,

Cosmos Yuqi Wang, Pu Zheng

et al.

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 26, 2025

3D organization of the genome plays a critical role in regulating gene expression. How 3D-genome differs among different cell types and relates to type–dependent transcriptional regulation remains unclear. Here, we used genome-scale DNA RNA imaging investigate transcriptionally distinct mouse cerebral cortex. We uncovered wide spectrum differences nuclear architecture types, ranging from size nucleus higher-order chromosome structures radial positioning chromatin loci within nucleus. These variations exhibit strong correlations with both total activity type–specific marker genes. Moreover, found that methylated binding protein MeCP2 promotes active-inactive segregation regulates transcription position–dependent manner is highly correlated its function modulating compartmentalization.

Language: Английский

Citations

3
CBP/p300: Critical Co-Activators for Nuclear Steroid Hormone Receptors and Emerging Therapeutic Targets in Prostate and Breast Cancers DOI Open Access
Aaron Waddell, Haojie Huang, Daiqing Liao

et al.

Cancers, Journal Year: 2021, Volume and Issue: 13(12), P. 2872 - 2872

Published: June 8, 2021

The CREB-binding protein (CBP) and p300 are two paralogous lysine acetyltransferases (KATs) that were discovered in the 1980s-1990s. Since their discovery, CBP/p300 have emerged as important regulatory proteins due to ability acetylate histone non-histone modulate transcription. Work last 20 years has firmly established critical regulators for nuclear hormone signaling pathways, which drive tumor growth several cancer types. Indeed, co-activators androgen receptor (AR) estrogen (ER) prostate breast cancer, respectively. AR ER stimulated by sex hormones function transcription factors regulate genes involved cell cycle progression, metabolism, other cellular functions contribute oncogenesis. Recent structural studies of AR/p300 ER/p300 complexes provided insights into mechanism interacts with activates AR- ER-mediated Breast rank first forth respectively diagnoses worldwide effective treatments urgently needed. efforts identified specific potent inhibitors target acetyltransferase activity acetytllysine-binding bromodomain (BD) CBP/p300. These compounds inhibit cancer. may also be applicable treating hormone-dependent cancers. Here we provide an in-depth account roles regulating pathways discuss potential

Language: Английский

Citations

76