Epigenetic control of Topoisomerase 1 activity presents a cancer vulnerability.

DNA transactions introduce torsional constraints that pose an inherent risk to genome integrity. While topoisomerase 1 (TOP1) activity is essential for removing DNA supercoiling, aberrant stabilization of TOP1:DNA cleavage complexes (TOP1ccs) can result in cytotoxic DNA lesions. What protects genomic hot spots of topological stress from aberrant TOP1 activity remains unknown.

Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma.

Childhood neuroblastoma with MYCN amplification is classified as high risk and often relapses after intensive treatments. Immune checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in patients with neuroblastoma, and the cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody nivolumab.

Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome.

MacroH2A has been linked to transcriptional silencing, cell identity, and is a hallmark of the inactive X chromosome (Xi). However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown/knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down replication progression rate in the Xi reflecting the higher nucleosome stability.

A FACT about macroH2A removal in immune gene activation.

Histone variants contribute to epigenetic regulation in development and disease but require the chaperone machinery for correct deposition. In this issue of Molecular Cell, Ji et al. explain how the chaperone complex FACT removes the histone variant macroH2A1.

The consequences of cohesin mutations in myeloid malignancies.

Recurrent somatic mutations in the genes encoding the chromatin-regulatory cohesin complex and its modulators occur in a wide range of human malignancies including a high frequency in myeloid neoplasms. The cohesin complex has a ring-like structure which can enclose two strands of DNA. A first function for the complex was described in sister chromatid cohesion during metaphase avoiding defects in chromosome segregation.

regioneReloaded: evaluating the association of multiple genomic region sets.

Motivation: Next-generation sequencing methods continue improving the annotation of genomes in part by determining the distribution of features such as epigenetic marks. Evaluating and interpreting the association between genomic regions and their features has become a common and challenging analysis in genomic and epigenomic studies.

Results: With regioneR we provided an R package allowing to assess the statistical significance of pairwise associations between genomic region sets using permutation tests.

Histone Variants and Their Chaperones in Hematological Malignancies.

Epigenetic regulation occurs on the level of compacting DNA into chromatin. The functional unit of chromatin is the nucleosome, which consists of DNA wrapped around a core of histone proteins. While canonical histone proteins are incorporated into chromatin through a replication-coupled process, structural variants of histones, commonly named histone variants, are deposited into chromatin in a replication-independent manner.

Different Gene Sets Are Associated With Azacitidine Response In Vitro Versus in Myelodysplastic Syndrome Patients.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by dysplasia, ineffective hematopoiesis, and predisposition to secondary acute myeloid leukemias (sAML). Azacitidine (AZA) is the standard care for high-risk MDS patients not eligible for allogenic bone marrow transplantation. However, only half of the patients respond to AZA and eventually all patients relapse.

The high mobility group protein HMG20A cooperates with the histone reader PHF14 to modulate TGFβ and Hippo pathways.

High mobility group (HMG) proteins are chromatin regulators with essential functions in development, cell differentiation and cell proliferation. The protein HMG20A is predicted by the AlphaFold2 software to contain three distinct structural elements, which we have functionally characterized: i) an amino-terminal, intrinsically disordered domain with transactivation activity; ii) an HMG box with higher binding affinity for double-stranded, four-way-junction DNA than for linear DNA; and iii) a long coiled-coil domain. Our proteomic study followed by a deletion analysis and structural modeling demonstrates that HMG20A forms a complex with the histone reader PHF14, via the establishment of a two-stranded alpha-helical coiled-coil structure.

MacroH2As regulate enhancer-promoter contacts affecting enhancer activity and sensitivity to inflammatory cytokines.

MacroH2A histone variants have a function in gene regulation that is poorly understood at the molecular level. We report that macroH2A1.2 and macroH2A2 modulate the transcriptional ground state of cancer cells and how they respond to inflammatory cytokines.

3D chromatin remodelling in the germ line modulates genome evolutionary plasticity.

Chromosome folding has profound impacts on gene regulation, whose evolutionary consequences are far from being understood. Here we explore the relationship between 3D chromatin remodelling in mouse germ cells and evolutionary changes in genome structure. Using a comprehensive integrative computational analysis, we (i) reconstruct seven ancestral rodent genomes analysing whole-genome sequences of 14 species representatives of the major phylogroups, (ii) detect lineage-specific chromosome rearrangements and (iii) identify the dynamics of the structural and epigenetic properties of evolutionary breakpoint regions (EBRs) throughout mouse spermatogenesis.

Evolution, structure and function of divergent macroH2A1 splice isoforms.

The replacement of replication-coupled histones with non-canonical histone variants provides chromatin with additional properties and contributes to the plasticity of the epigenome. MacroH2A histone variants are counterparts of the replication-coupled histone H2A. They are characterized by a unique tripartite structure, consisting of a histone fold, an unstructured linker, and a globular macrodomain.

Histone Modifications and Their Targeting in Lymphoid Malignancies.

In a wide range of lymphoid neoplasms, the process of malignant transformation is associated with somatic mutations in B cells that affect the epigenetic machinery. Consequential alterations in histone modifications contribute to disease-specific changes in the transcriptional program. Affected genes commonly play important roles in cell cycle regulation, apoptosis-inducing signal transduction, and DNA damage response, thus facilitating the emergence of malignant traits that impair immune surveillance and favor the emergence of different B-cell lymphoma subtypes.

Divergent leukaemia subclones as cellular models for testing vulnerabilities associated with gains in chromosomes 7, 8 or 18.

Haematopoietic malignancies are frequently characterized by karyotypic abnormalities. The development of targeted drugs has been pioneered with compounds against gene products of fusion genes caused by chromosomal translocations. While polysomies are equally frequent as translocations, for many of them we are lacking therapeutic approaches aimed at synthetic lethality.

Inhibition of CBP synergizes with the RNA-dependent mechanisms of Azacitidine by limiting protein synthesis.

The nucleotide analogue azacitidine (AZA) is currently the best treatment option for patients with high-risk myelodysplastic syndromes (MDS). However, only half of treated patients respond and of these almost all eventually relapse. New treatment options are urgently needed to improve the clinical management of these patients.

The Histone Variant MacroH2A1 Impacts Circadian Gene Expression and Cell Phenotype in an In Vitro Model of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. A foremost risk factor for HCC is obesity/metabolic syndrome-related non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which is prompted by remarkable changes in transcription patterns of genes enriching metabolic, immune/inflammatory, and circadian pathways. Epigenetic mechanisms play a role in NAFLD-associated HCC, and macroH2A1, a variant of histone H2A, is involved in the pathogenesis modulating the expression of oncogenes and/or tumor suppressor genes and interacting with SIRT1, which crucially impacts the circadian clock circuitry.

The Role of MacroH2A Histone Variants in Cancer.

The epigenome regulates gene expression and provides a molecular memory of cellular events. A growing body of evidence has highlighted the importance of epigenetic regulation in physiological tissue homeostasis and malignant transformation. Among epigenetic mechanisms, the replacement of replication-coupled histones with histone variants is the least understood.

Disruption of paternal circadian rhythm affects metabolic health in male offspring via nongerm cell factors.

Circadian rhythm synchronizes each body function with the environment and regulates physiology. Disruption of normal circadian rhythm alters organismal physiology and increases disease risk. Recent epidemiological data and studies in model organisms have shown that maternal circadian disruption is important for offspring health and adult phenotypes.

Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions.

The histone demethylase KDM5A erases histone H3 lysine 4 methylation, which is involved in transcription and DNA damage responses (DDRs). While DDR functions of KDM5A have been identified, how KDM5A recognizes DNA lesion sites within chromatin is unknown. Here, we identify two factors that act upstream of KDM5A to promote its association with DNA damage sites.

Epigenetics in a Spectrum of Myeloid Diseases and Its Exploitation for Therapy.

Mutations in genes encoding chromatin regulators are early events contributing to developing asymptomatic clonal hematopoiesis of indeterminate potential and its frequent progression to myeloid diseases with increasing severity. We focus on the subset of myeloid diseases encompassing myelodysplastic syndromes and their transformation to secondary acute myeloid leukemia. We introduce the major concepts of chromatin regulation that provide the basis of epigenetic regulation.

Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival.

Background: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic.