Mutant NPM1 Hijacks Transcriptional Hubs to Maintain Pathogenic Gene Programs in Acute Myeloid Leukemia.

Unlabelled: Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein with a wide range of biological functions. In 30% of acute myeloid leukemia (AML), the terminal exon of NPM1 is often found mutated, resulting in the addition of a nuclear export signal and a shift of the protein to the cytoplasm (NPM1c). AMLs carrying this mutation have aberrant expression of the HOXA/B genes, whose overexpression leads to leukemogenic transformation.

Connecting high-resolution 3D chromatin organization with epigenomics.

The resolution of chromatin conformation capture technologies keeps increasing, and the recent nucleosome resolution chromatin contact maps allow us to explore how fine-scale 3D chromatin organization is related to epigenomic states in human cells. Using publicly available Micro-C datasets, we develop a deep learning model, CAESAR, to learn a mapping function from epigenomic features to 3D chromatin organization. The model accurately predicts fine-scale structures, such as short-range chromatin loops and stripes, that Hi-C fails to detect.

3'HS1 CTCF binding site in human β-globin locus regulates fetal hemoglobin expression.

Mutations in the adult β-globin gene can lead to a variety of hemoglobinopathies, including sickle cell disease and β-thalassemia. An increase in fetal hemoglobin expression throughout adulthood, a condition named hereditary persistence of fetal hemoglobin (HPFH), has been found to ameliorate hemoglobinopathies. Deletional HPFH occurs through the excision of a significant portion of the 3' end of the β-globin locus, including a CTCF binding site termed 3'HS1.

Profiling Chromatin Landscape at High Resolution and Throughput with 2C-ChIP.

Chromatin immunoprecipitation (ChIP) is used to probe the presence of proteins and/or their posttranslational modifications on genomic DNA. This method is often used alongside chromosome conformation capture approaches to obtain a better-rounded view of the functional relationship between chromatin architecture and its landscape. Since the inception of ChIP, its protocol has been modified to improve speed, sensitivity, and specificity.

Dnmt3a loss and Idh2 neomorphic mutations mutually potentiate malignant hematopoiesis.

Mutations in the epigenetic regulators DNMT3A and IDH1/2 co-occur in patients with acute myeloid leukemia and lymphoma. In this study, these 2 epigenetic mutations cooperated to induce leukemia. Leukemia-initiating cells from Dnmt3a-/- mice that express an IDH2 neomorphic mutant have a megakaryocyte-erythroid progenitor-like immunophenotype, activate a stem-cell-like gene signature, and repress differentiated progenitor genes.

2C-ChIP: measuring chromatin immunoprecipitation signal from defined genomic regions with deep sequencing.

Background: Understanding how transcription occurs requires the integration of genome-wide and locus-specific information gleaned from robust technologies. Chromatin immunoprecipitation (ChIP) is a staple in gene expression studies, and while genome-wide methods are available, high-throughput approaches to analyze defined regions are lacking.

Results: Here, we present carbon copy-ChIP (2C-ChIP), a versatile, inexpensive, and high-throughput technique to quantitatively measure the abundance of DNA sequences in ChIP samples.

Chromosome folding and its regulation in health and disease.

There are many ways in which cells may not adequately behave or respond to their environment, and the molecular mechanisms leading to these defects are as diverse as they are many. In this review, we report on how spatial chromatin organization contributes to the proper expression of genes, relating how CTCF-one of its main architects-contributes to gene regulation. We also touch on the emerging role of long noncoding RNAs in shaping chromatin organization and activity.

Spatial Organization of Epigenomes.

The role of genome architecture in transcription regulation has become the focus of an increasing number of studies over the past decade. Chromatin organization can have a significant impact on gene expression by promoting or restricting the physical proximity between regulatory DNA elements. Given that any change in chromatin state has the potential to alter DNA folding and the proximity between control elements, the spatial organization of chromatin is inherently linked to its molecular composition.

Chromatin conformation signatures: ideal human disease biomarkers?

Human health is related to information stored in our genetic code, which is highly variable even amongst healthy individuals. Gene expression is orchestrated by numerous control elements that may be located anywhere in the genome, and can regulate distal genes by physically interacting with them. These DNA contacts can be mapped with the chromosome conformation capture and related technologies.

The three-dimensional architecture of Hox cluster silencing.

Spatial chromatin organization is emerging as an important mechanism to regulate the expression of genes. However, very little is known about genome architecture at high-resolution in vivo. Here, we mapped the three-dimensional organization of the human Hox clusters with chromosome conformation capture (3C) technology.