Molecular Portraits of Social Adversity in Breast Cancer: Neighborhood Disadvantage is Associated with Epigenetic Deregulation of Key Oncogenic Pathways.

Background: Social adversity from neighborhood disadvantage (ND) is associated with shorter breast cancer (BCa)-survival (BCSS). Although studies have identified associations between ND and DNA methylation (DNAme) or gene expression (mRNA), a study integrating DNAme and mRNA to understand how the epigenome regulates key biological pathways in ND, merits further inquiry.

Methods: DNAme, mRNA, miRNA, and tRNA-derived fragment data were analyzed from 80 ER+/HER2- BCa samples.

Integrator promotes the association of TFIID and RNA polymerase II to maintain pluripotency during development.

The mechanisms by which the expression of pluripotency and Polycomb networks are harmonized to allow the transition from pluripotency to a differentiated state have not been fully elucidated. Integrator complex regulates transcription pause release and RNA processing in metazoans. We show that Integrator is required for stemness and plays a critical role as early as day 2 in embryonic development.

Bypass of Blocking Lesions by RNAPII Impairs the Transcriptional DNA Damage Response.

Ultraviolet (UV) irradiation and platinum-based drugs generate bulky DNA lesions that impede transcription elongation by RNA Polymerase II (RNAPII). This transcriptional block triggers a coordinated stress response involving transcription-coupled nucleotide excision repair (TC-NER), removal and degradation of the stalled RNAPII, and global transcriptional shutdown. However, the molecular and cellular consequences of RNAPII bypassing such lesions remain unclear.

Genome-wide methylome modeling via generative AI incorporating long- and short-range interactions.

Using millions of methylation segments, we developed DiffuCpG, a generative artificial intelligence (AI) diffusion model designed to solve the critical challenge of missing data in high-throughput methylation technologies. DiffuCpG goes beyond conventional methods by leveraging both short-range interactions including nearby CpGs from both latitude and longitude of the dataset, local DNA sequences, and long-range interactions, including three-dimensional genome architecture and long-distance correlations, to comprehensively model the methylome. Compared to previous methods, through extensive independent validations across different tissue types, cancers, and technologies (whole-genome bisulfite sequencing, enhanced reduced representation bisulfite sequencing, single-cell bisulfite sequencing, and methylation arrays), DiffuCpG has demonstrated superior performance in accuracy, scalability, and versatility.

A nucleosome switch primes hepatitis B virus infection.

Chronic hepatitis B virus (HBV) infection is an incurable pathogen responsible for causing liver disease and hepatocellular carcinoma. During the genesis of infection, HBV establishes an independent minichromosome consisting of the viral covalently closed circular DNA (cccDNA) genome and host histones. The viral X gene must be expressed immediately upon infection to induce degradation of the host silencing factor, the Smc5/6 complex.

Fine-tuning of gene expression through the Mettl3-Mettl14-Dnmt1 axis controls ESC differentiation.

The marking of DNA, histones, and RNA is central to gene expression regulation in development and disease. Recent evidence links N6-methyladenosine (mA), installed on RNA by the METTL3-METTL14 methyltransferase complex, to histone modifications, but the link between mA and DNA methylation remains scarcely explored. This study shows that METTL3-METTL14 recruits the DNA methyltransferase DNMT1 to chromatin for gene-body methylation.

Histone H3 mutations and their impact on genome stability maintenance.

Histones are essential for maintaining chromatin structure and function. Histone mutations lead to changes in chromatin compaction, gene expression, and the recruitment of DNA repair proteins to the DNA lesion. These disruptions can impair critical DNA repair pathways, such as homologous recombination and non-homologous end joining, resulting in increased genomic instability, which promotes an environment favorable to tumor development and progression.

C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer.

In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC, the Notch ligand JAG1, and ANGPTL4.

Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3.

Polycomb repressive complex 2 regulates basal cell fate during adult olfactory neurogenesis.

Adult neurogenesis occurs in the mammalian olfactory epithelium to maintain populations of neurons that are vulnerable to injury yet essential for olfaction. Multipotent olfactory basal stem cells are activated by damage, although mechanisms regulating lineage decisions are not understood. Using mouse lesion models, we focused on defining the role of Polycomb repressive complexes (PRCs) in olfactory neurogenesis.

The SWI/SNF chromatin-remodeling subunit DPF2 facilitates NRF2-dependent antiinflammatory and antioxidant gene expression.

During emergency hematopoiesis, hematopoietic stem cells (HSCs) rapidly proliferate to produce myeloid and lymphoid effector cells, a response that is critical against infection or tissue injury. If unresolved, this process leads to sustained inflammation, which can cause life-threatening diseases and cancer. Here, we identify a role of double PHD fingers 2 (DPF2) in modulating inflammation.

Endocrine resistance and breast cancer plasticity are controlled by CoREST.

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway.

Know when to fold 'em: Polycomb complexes in oncogenic 3D genome regulation.

Chromatin is spatially and temporally regulated through a series of orchestrated processes resulting in the formation of 3D chromatin structures such as topologically associating domains (TADs), loops and Polycomb Bodies. These structures are closely linked to transcriptional regulation, with loss of control of these processes a frequent feature of cancer and developmental syndromes. One such oncogenic disruption of the 3D genome is through recurrent dysregulation of Polycomb Group Complex (PcG) functions either through genetic mutations, amplification or deletion of genes that encode for PcG proteins.

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCOR CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC).

The Polycomb protein RING1B enables estrogen-mediated gene expression by promoting enhancer-promoter interaction and R-loop formation.

Polycomb complexes have traditionally been prescribed roles as transcriptional repressors, though increasing evidence demonstrate they can also activate gene expression. However, the mechanisms underlying positive gene regulation mediated by Polycomb proteins are poorly understood. Here, we show that RING1B, a core component of Polycomb Repressive Complex 1, regulates enhancer-promoter interaction of the bona fide estrogen-activated GREB1 gene.

Epigenetic mechanisms in breast cancer therapy and resistance.

The majority of breast cancers express the estrogen receptor (ERα) and agents targeting this pathway represent the main treatment modality. Endocrine therapy has proven successful in the treatment of hormone-responsive breast cancer since its early adoption in the 1940s as an ablative therapy. Unfortunately, therapeutic resistance arises, leading to disease recurrence and relapse.

Clinical Responsiveness to All-trans Retinoic Acid Is Potentiated by LSD1 Inhibition and Associated with a Quiescent Transcriptome in Myeloid Malignancies.

Purpose: In preclinical studies, the lysine-specific histone demethylase 1A (LSD1) inhibitor tranylcypromine (TCP) combined with all-trans retinoic acid (ATRA) induces differentiation and impairs survival of myeloid blasts in non-acute promyelocytic leukemia acute myeloid leukemia (AML). We conducted a phase I clinical trial (NCT02273102) to evaluate the safety and activity of ATRA plus TCP in patients with relapsed/refractory AML and myelodysplasia (MDS).

Patients And Methods: Seventeen patients were treated with ATRA and TCP (three dose levels: 10 mg twice daily, 20 mg twice daily, and 30 mg twice daily).

Estrogen induces dynamic ERα and RING1B recruitment to control gene and enhancer activities in luminal breast cancer.

RING1B, a core Polycomb repressive complex 1 subunit, is a histone H2A ubiquitin ligase essential for development. RING1B is overexpressed in patients with luminal breast cancer (BC) and recruited to actively transcribed genes and enhancers co-occupied by the estrogen receptor α (ERα). Whether ERα-induced transcriptional programs are mediated by RING1B is not understood.

PDGFRA defines the mesenchymal stem cell Kaposi's sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment.

Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis.

Emerging Roles for Polycomb-Group Proteins in Stem Cells and Cancer.

Polycomb-group (PcG) complexes are multiprotein, evolutionarily conserved epigenetic machineries that regulate stem cell fate decisions and development, and are also implicated in cancer and other maladies. The PcG machinery can be divided into two major complexes: Polycomb repressive complex 1 and 2 (PRC1 and PRC2). Traditionally, PcG complexes have been associated with maintenance of gene repression mainly via histone-modifying activities.

p27 transcriptionally coregulates cJun to drive programs of tumor progression.

p27 shifts from CDK inhibitor to oncogene when phosphorylated by PI3K effector kinases. Here, we show that p27 is a cJun coregulator, whose assembly and chromatin association is governed by p27 phosphorylation. In breast and bladder cancer cells with high p27pT157pT198 or expressing a CDK-binding defective p27pT157pT198 phosphomimetic (p27CK-DD), cJun is activated and interacts with p27, and p27/cJun complexes localize to the nucleus.

Polycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms.

Polycomb repressive complex 1 (PRC1) plays essential roles in cell fate decisions and development. However, its role in cancer is less well understood. Here, we show that RNF2, encoding RING1B, and canonical PRC1 (cPRC1) genes are overexpressed in breast cancer.

The Polycomb group protein CBX6 is an essential regulator of embryonic stem cell identity.

Polycomb group proteins (PcG) are transcriptional repressors that control cell identity and development. In mammals, five different CBX proteins associate with the core Polycomb repressive complex 1 (PRC1). In mouse embryonic stem cells (ESCs), CBX6 and CBX7 are the most highly expressed CBX family members.