The genetic information of human cells is stored in the context of chromatin, which is subjected to DNA methylation and various histone modifications. Such a 'language' of chromatin modification constitutes a fundamental means of gene and (epi)genome regulation, underlying a myriad of cellular and developmental processes. In recent years, mounting evidence has demonstrated that miswriting, misreading or mis-erasing of the modification language embedded in chromatin represents a common, sometimes early and pivotal, event across a wide range of human cancers, contributing to oncogenesis through the induction of epigenetic, transcriptomic and phenotypic alterations. It is increasingly clear that cancer-related metabolic perturbations and oncohistone mutations also directly impact chromatin modification, thereby promoting cancerous transformation. Phase separation-based deregulation of chromatin modulators and chromatin structure is also emerging to be an important underpinning of tumorigenesis. Understanding the various molecular pathways that underscore a misregulated chromatin language in cancer, together with discovery and development of more effective drugs to target these chromatin-related vulnerabilities, will enhance treatment of human malignancies.

The language of chromatin modification in human cancers.

Our understanding﻿ of the ubiquitin code has greatly evolved from conventional E1, E2 and E3 enzymes that modify Lys residues on specific substrates with a single type of ubiquitin chain to more complex processes that regulate and mediate ubiquitylation. In this Review, we discuss recently discovered endogenous mechanisms and unprecedented pathways by which pathogens rewrite the ubiquitin code to promote infection. These processes include unconventional ubiquitin modifications involving ester linkages with proteins, lipids and sugars, or ubiquitylation through a phosphoribosyl bridge involving Arg42 of ubiquitin. We also introduce the enzymatic pathways that write and reverse these modifications, such as the papain-like proteases of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2. Furthermore, structural studies have revealed that the ultimate functions of ubiquitin are mediated not simply by straightforward recognition by ubiquitin-binding domains. Instead, elaborate multivalent interactions between ubiquitylated targets or ubiquitin chains and their readers (for example, the proteasome, the MLL1 complex or DOT1L) can elicit conformational changes that regulate protein degradation or transcription. The newly discovered mechanisms provide opportunities for innovative therapeutic interventions for diseases such as cancer and infectious diseases. 

/pdf/an-expanded-lexicon-for-the-ubiquitin-code-14uc85w9.pdf

An expanded lexicon for the ubiquitin code

Epigenetics regulates gene expression and has been confirmed to play a critical role in a variety of metabolic diseases, such as diabetes, obesity, non-alcoholic fatty liver disease (NAFLD), osteoporosis, gout, hyperthyroidism, hypothyroidism and others. The term 'epigenetics' was firstly proposed in 1942 and with the development of technologies, the exploration of epigenetics has made great progresses. There are four main epigenetic mechanisms, including DNA methylation, histone modification, chromatin remodelling, and noncoding RNA (ncRNA), which exert different effects on metabolic diseases. Genetic and non-genetic factors, including ageing, diet, and exercise, interact with epigenetics and jointly affect the formation of a phenotype. Understanding epigenetics could be applied to diagnosing and treating metabolic diseases in the clinic, including epigenetic biomarkers, epigenetic drugs, and epigenetic editing. In this review, we introduce the brief history of epigenetics as well as the milestone events since the proposal of the term 'epigenetics'. Moreover, we summarise the research methods of epigenetics and introduce four main general mechanisms of epigenetic modulation. Furthermore, we summarise epigenetic mechanisms in metabolic diseases and introduce the interaction between epigenetics and genetic or non-genetic factors. Finally, we introduce the clinical trials and applications of epigenetics in metabolic diseases. 

/pdf/epigenetic-regulation-in-metabolic-diseases-mechanisms-and-1cgyfqq2.pdf

Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study

Methyltransferases of the mixed-lineage leukaemia (MLL) family—which include MLL1, MLL2, MLL3, MLL4, SET1A and SET1B—implement methylation of histone H3 on lysine 4 (H3K4), and have critical and distinct roles in the regulation of transcription in haematopoiesis, adipogenesis and development1–6. The C-terminal catalytic SET (Su(var.)3-9, enhancer of zeste and trithorax) domains of MLL proteins are associated with a common set of regulatory factors (WDR5, RBBP5, ASH2L and DPY30) to achieve specific activities7–9. Current knowledge of the regulation of MLL activity is limited to the catalysis of histone H3 peptides, and how H3K4 methyl marks are deposited on nucleosomes is poorly understood. H3K4 methylation is stimulated by mono-ubiquitination of histone H2B on lysine 120 (H2BK120ub1), a prevalent histone H2B mark that disrupts chromatin compaction and favours open chromatin structures, but the underlying mechanism remains unknown10–12. Here we report cryo-electron microscopy structures of human MLL1 and MLL3 catalytic modules associated with nucleosome core particles that contain H2BK120ub1 or unmodified H2BK120. These structures demonstrate that the MLL1 and MLL3 complexes both make extensive contacts with the histone-fold and DNA regions of the nucleosome; this allows ease of access to the histone H3 tail, which is essential for the efficient methylation of H3K4. The H2B-conjugated ubiquitin binds directly to RBBP5, orienting the association between MLL1 or MLL3 and the nucleosome. The MLL1 and MLL3 complexes display different structural organizations at the interface between the WDR5, RBBP5 and MLL1 (or the corresponding MLL3) subunits, which accounts for the opposite roles of WDR5 in regulating the activity of the two enzymes. These findings transform our understanding of the structural basis for the regulation of MLL activity at the nucleosome level, and highlight the pivotal role of nucleosome regulation in histone-tail modification. Cryo-electron microscopy structures of mixed-lineage leukaemia methyltransferases 1 and 3 associated with unmodified or mono-ubiquitinated nucleosome reveal the structural basis for the activity specificity and regulation of these enzymes.

Structural basis of nucleosome recognition and modification by MLL methyltransferases.

Protein lysine methylation is a crucial post-translational modification that regulates the functions of both histone and non-histone proteins. Deregulation of the enzymes or ‘writers’ of protein lysine methylation, lysine methyltransferases (KMTs), is implicated in the cause of many diseases, including cancer, mental health disorders and developmental disorders. Over the past decade, significant advances have been made in developing drugs to target KMTs that are involved in histone methylation and epigenetic regulation. The first of these inhibitors, tazemetostat, was recently approved for the treatment of epithelioid sarcoma and follicular lymphoma, and several more are in clinical and preclinical evaluation. Beyond chromatin, the many KMTs that regulate protein synthesis and other fundamental biological processes are emerging as promising new targets for drug development to treat diverse diseases. Protein lysine methylation is an important post-translational modification of histone and non-histone proteins. In this Review, Gozani and colleagues discuss the role of protein lysine methyltransferases, the ‘writers’ of protein lysine methylation, in a range of diseases, and the progress and potential of targeting these enzymes therapeutically. They also consider the biology of lysine methyltransferases beyond epigenetic regulation as emerging targets for drug discovery.

Epigenetics and beyond: targeting writers of protein lysine methylation to treat disease.

Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L

Methylation of histone H3, lysine 79 (H3K79), by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B at lysine 120 (H2B-Ub), and is a well-characterized example of histone modification cross-talk that is conserved from yeast to humans. The mechanism by which H2B-Ub stimulates Dot1L to methylate the relatively inaccessible histone core H3K79 residue is unknown. The 3.0 A resolution cryo-EM structure of Dot1L bound to ubiquitinated nucleosome reveals that Dot1L contains binding sites for both ubiquitin and the histone H4 tail, which establish two regions of contact that stabilize a catalytically competent state and positions the Dot1L active site over H3K79. We unexpectedly find that contacts mediated by both Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to project deep into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals an unexpected structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.

https://biorxiv.org/content/biorxiv/early/2018/12/19/501098.full-text.pdf

The mechanism of cross-talk between histone H2B ubiquitination and H3 methylation by Dot1L

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Niklas A. Hoffmann

Author Tools

Chat about Author

Papers

Mechanism of cross-talk between H2B ubiquitination and H3 methylation by Dot1L

The mechanism of cross-talk between histone H2B ubiquitination and H3 methylation by Dot1L