Chromatin hubs drive key regulatory networks in leukemia.

In this issue of Molecular Cell, Gambi, Boccalatte, Hernaez, et al. apply multiomics followed by genetic engineering to define then characterize epigenetic hubs that regulate processes crucial for T-ALL and use this insight to offer new avenues for therapeutic targeting.

Hijacked enhancer-promoter and silencer-promoter loops in cancer.

Recent work has shown that besides inducing fusion genes, structural variations (SVs) can also contribute to oncogenesis by disrupting the three-dimensional genome organization and dysregulating gene expression. At the chromatin-loop level, SVs can relocate enhancers or silencers from their original genomic loci to activate oncogenes or repress tumor suppressor genes. On a larger scale, different types of alterations in topologically associating domains (TADs) have been reported in cancer, such as TAD expansion, shuffling, and SV-induced neo-TADs.

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.

Background: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle.

Methods: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls.

HiCLift: a fast and efficient tool for converting chromatin interaction data between genome assemblies.

Motivation: With the continuous effort to improve the quality of human reference genome and the generation of more and more personal genomes, the conversion of genomic coordinates between genome assemblies is critical in many integrative and comparative studies. While tools have been developed for such task for linear genome signals such as ChIP-Seq, no tool exists to convert genome assemblies for chromatin interaction data, despite the importance of three-dimensional genome organization in gene regulation and disease.

Results: Here, we present HiCLift, a fast and efficient tool that can convert the genomic coordinates of chromatin contacts such as Hi-C and Micro-C from one assembly to another, including the latest T2T-CHM13 genome.

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

Background: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD.

Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA).

Insights into the nucleophilic substitution of pyridine at an unsaturated carbon center.

Bimolecular nucleophilic substitution (S2) is a fundamental reaction that has been widely studied. So far, the nucleophiles are mainly anionic species in S2 reactions. In this study, we use density functional theory calculations to assess the mechanisms of substitution of carbonyl, imidoyl, and vinyl compounds with a neutral nucleophile, pyridine.

Noncoding genetic variation in GATA3 increases acute lymphoblastic leukemia risk through local and global changes in chromatin conformation.

Inherited noncoding genetic variants confer significant disease susceptibility to childhood acute lymphoblastic leukemia (ALL) but the molecular processes linking germline polymorphisms with somatic lesions in this cancer are poorly understood. Through targeted sequencing in 5,008 patients, we identified a key regulatory germline variant in GATA3 associated with Philadelphia chromosome-like ALL (Ph-like ALL). Using CRISPR-Cas9 editing and samples from patients with Ph-like ALL, we showed that this variant activated a strong enhancer that upregulated GATA3 transcription.

Targeting the Metastasis Suppressor, N-Myc Downstream Regulated Gene-1, with Novel Di-2-Pyridylketone Thiosemicarbazones: Suppression of Tumor Cell Migration and Cell-Collagen Adhesion by Inhibiting Focal Adhesion Kinase/Paxillin Signaling.

Metastasis is a complex process that is regulated by multiple signaling pathways, with the focal adhesion kinase (FAK)/paxillin pathway playing a major role in the formation of focal adhesions and cell motility. N-myc downstream regulated gene-1 (NDRG1) is a potent metastasis suppressor in many solid tumor types, including prostate and colon cancer. Considering the antimetastatic effect of NDRG1 and the crucial involvement of the FAK/paxillin pathway in cellular migration and cell-matrix adhesion, we assessed the effects of NDRG1 on this important oncogenic pathway.