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Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyze cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single-cell analysis of human clinical samples exhibits a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall, our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy. Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

c-MYC (MYC) is a major driver of prostate cancer tumorigenesis and progression. Although MYC is overexpressed in both early and metastatic disease and associated with poor survival, its impact on prostate transcriptional reprogramming remains elusive. We demonstrate that MYC overexpression significantly diminishes the androgen receptor (AR) transcriptional program (the set of genes directly targeted by the AR protein) in luminal prostate cells without altering AR expression. Analyses of clinical specimens reveal that concurrent low AR and high MYC transcriptional programs accelerate prostate cancer progression toward a metastatic, castration-resistant disease. Data integration of single-cell transcriptomics together with ChIP-seq uncover an increase in RNA polymerase II (Pol II) promoter-proximal pausing at AR-dependent genes following MYC overexpression without an accompanying deactivation of AR-bound enhancers. Altogether, our findings suggest that MYC overexpression antagonizes the canonical AR transcriptional program and contributes to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes. The role of MYC in transcriptional reprogramming in prostate cancer remains poorly characterized. Here, MYC overexpression antagonizes the canonical AR transcriptional program leading to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

We present Model-based AnalysEs of Transcriptome and RegulOme (MAESTRO), a comprehensive open-source computational workflow ( http://github.com/liulab-dfci/MAESTRO ) for the integrative analyses of single-cell RNA-seq (scRNA-seq) and ATAC-seq (scATAC-seq) data from multiple platforms. MAESTRO provides functions for pre-processing, alignment, quality control, expression and chromatin accessibility quantification, clustering, differential analysis, and annotation. By modeling gene regulatory potential from chromatin accessibilities at the single-cell level, MAESTRO outperforms the existing methods for integrating the cell clusters between scRNA-seq and scATAC-seq. Furthermore, MAESTRO supports automatic cell-type annotation using predefined cell type marker genes and identifies driver regulators from differential scRNA-seq genes and scATAC-seq peaks.

Chromatin organization is a highly orchestrated process that influences gene expression, in part by modulating access of regulatory factors to DNA and nucleosomes. Here, we report that the chromatin accessibility regulator HMGN1, a target of recurrent DNA copy gains in leukemia, controls myeloid differentiation. HMGN1 amplification is associated with increased accessibility, expression, and histone H3K27 acetylation of loci important for hematopoietic stem cells (HSCs) and leukemia, such as HoxA cluster genes. In vivo, HMGN1 overexpression is linked to decreased quiescence and increased HSC activity in bone marrow transplantation. HMGN1 overexpression also cooperates with the AML-ETO9a fusion oncoprotein to impair myeloid differentiation and enhance leukemia stem cell (LSC) activity. Inhibition of histone acetyltransferases CBP/p300 relieves the HMGN1-associated differentiation block. These data nominate factors that modulate chromatin accessibility as regulators of HSCs and LSCs, and suggest that targeting HMGN1 or its downstream effects on histone acetylation could be therapeutically active in AML. Chromatin accessibility is a key mediator of gene expression and mutations in chromatin modifiers are frequently seen in cancers. Here, the authors show that the chromatin accessibility regulator HMGN1 - which is frequently mutated by amplification in leukemias - acts by blocking myeloid differentiation.

Fixed-tissue ChIP-seq for H3K27 acetylation (H3K27ac) profiling (FiTAc-seq) is an epigenetic method for profiling active enhancers and promoters in formalin-fixed, paraffin-embedded (FFPE) tissues. We previously developed a modified ChIP-seq protocol (FiT-seq) for chromatin profiling in FFPE. FiT-seq produces high-quality chromatin profiles particularly for methylated histone marks but is not optimized for H3K27ac profiling. FiTAc-seq is a modified protocol that replaces the proteinase K digestion applied in FiT-seq with extended heating at 65 °C in a higher concentration of detergent and a minimized sonication step, to produce robust genome-wide H3K27ac maps from clinical samples. FiTAc-seq generates high-quality enhancer landscapes and super-enhancer (SE) annotation in numerous archived FFPE samples from distinct tumor types. This approach will be of great interest for both basic and clinical researchers. The entire protocol from FFPE blocks to sequence-ready library can be accomplished within 4 d. This protocol describes a ChIP-seq procedure optimized for profiling H3K27 acetylation in archived formalin-fixed, paraffin-embedded (FFPE) tissues sampled through whole or macrodissected sectioning or from punched cores.

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies. The response of prostate cancer cells to androgens depends on the dose. Here, the authors show that low levels of androgens function through androgen receptor (AR) monomers to activate mTOR and promote cell proliferation, while high dose androgens induce AR dimerization to inhibit c-MYC expression and facilitate cell differentiation.

Esophageal squamous cell carcinomas (ESCCs) harbor recurrent chromosome 3q amplifications that target the transcription factor SOX2. Beyond its role as an oncogene in ESCC, SOX2 acts in development of the squamous esophagus and maintenance of adult esophageal precursor cells. To compare Sox2 activity in normal and malignant tissue, we developed engineered murine esophageal organoids spanning normal esophagus to Sox2 -induced squamous cell carcinoma and mapped Sox2 binding and the epigenetic and transcriptional landscape with evolution from normal to cancer. While oncogenic Sox2 largely maintains actions observed in normal tissue, Sox2 overexpression with p53 and p16 inactivation promotes chromatin remodeling and evolution of the Sox2 cistrome. With Klf5 , oncogenic Sox2 acquires new binding sites and enhances activity of oncogenes such as Stat3 . Moreover, oncogenic Sox2 activates endogenous retroviruses, inducing expression of double-stranded RNA and dependence on the RNA editing enzyme ADAR1. These data reveal SOX2 functions in ESCC, defining targetable vulnerabilities. The transition from normal esophageal tissue to squamous carcinoma is characterized by an altered SOX2 cistrome. This transcriptional reprogramming activates endogenous retroviruses and double-stranded RNA expression, creating a dependency on the RNA editing enzyme ADAR1.

Climate change and rapid urbanization are intensifying global environmental challenges, particularly the nexus of urban heat stress and air pollution, which collectively impact human health and outdoor livability. This study investigates the spatiotemporal distribution of the outdoor thermal environment and PM2.5 concentrations in residential areas of Wuhan, a city with a hot-summer–cold-winter climate, and evaluates their combined effects on outdoor thermal comfort. Field measurements of microclimatic parameters and PM2.5 levels were conducted in two typical residential communities during winter and summer, supplemented by 582 valid questionnaires to assess residents’ subjective thermal responses. Key findings include (1) residents’ satisfaction decreases by approximately 1 unit for every 90-unit increase in AQI, and PM2.5 concentrations can effectively substitute for AQI in characterizing the impact of air quality on satisfaction. (2) The explanatory power of the UTCI-MTSV model (R2: 0.3152–0.7763) is pollutant-dependent; winter thermal comfort adheres to the linear law of UTCI, while dispersed summer votes indicate a non-linear effect of PM2.5 on comfort. (3) Wuhan residents show high thermal tolerance across AQIs. The lower limits of the Thermal Acceptability Range (TAR) are 7.1 °C (AQI-I) and 8.8 °C (AQI-II), both below neutral ranges, while the summer TAR-UTCI is 30.9 °C (above the neutral range). Better air quality improves the reliability of the thermal acceptability–UTCI fit. (4) TCV peaks at approximately 16 °C, increasing then decreasing with UTCI; at identical UTCI levels, better air quality enhances comfort, particularly within the 0–10 °C range. This study provides empirical evidence to inform urban design strategies for mitigating heat stress and pollution in hot-summer–cold-winter regions.

How cancer cells adapt to evade the therapeutic effects of drugs targeting oncogenic drivers is poorly understood. Here we report an epigenetic mechanism leading to the adaptive resistance of triple-negative breast cancer (TNBC) to fibroblast growth factor receptor (FGFR) inhibitors. Prolonged FGFR inhibition suppresses the function of BRG1-dependent chromatin remodelling, leading to an epigenetic state that derepresses YAP-associated enhancers. These chromatin changes induce the expression of several amino acid transporters, resulting in increased intracellular levels of specific amino acids that reactivate mTORC1. Consistent with this mechanism, addition of mTORC1 or YAP inhibitors to FGFR blockade synergistically attenuated the growth of TNBC patient-derived xenograft models. Collectively, these findings reveal a feedback loop involving an epigenetic state transition and metabolic reprogramming that leads to adaptive therapeutic resistance and provides potential therapeutic strategies to overcome this mechanism of resistance. Li et al. define an adaptive resistance mechanism against FGFR inhibitor treatment in breast cancer attributed to loss of BRG1 chromatin recruitment, reactivation of YAP-dependent enhancers and upregulation of amino acid-induced mTORC1 activity.

Background. circRNAs are part of the competitive endogenous RNA network, which putatively function as miRNA sponges and play a crucial role in the development of numerous diseases. However, studies of circRNAs in rheumatoid arthritis (RA) disease are limited. This work aims to identify the expression pattern of circRNAs in synovial tissues and their inflammatory regulation mechanism. Methods. We first compared the mRNA expression in rheumatoid arthritis patients with that in healthy volunteers by GEO database mining to identify gene loci specifically expressed in synovial tissues. Functional enrichment algorithms were then used to draw the interactome diagram of circRNAs-miRNAs-mRNAs. Finally, loss-of-function and rescue assays of the candidate circRNAs were performed in vitro. Results. A total of 29 differentially expressed circRNAs related to rheumatoid arthritis were discovered. Silencing of hsa_circ_0001859 suppressed ATF2 expression and decreased inflammatory activity in SW982 cells. Hsa_circ_0001859 could compete with ATF2 for miR-204/211. Discussion. These findings indicate that hsa_circ_0001859 participates deeply in the process of chronic inflammatory disease in synovial tissue.