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Background The development of secondary resistance (SR) in metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (anti-EGFR) antibodies is not fully understood at the molecular level. Here we tested in vivo selection of anti-EGFR SR tumors in CRC patient-derived xenograft (PDX) models as a strategy for a molecular dissection of SR mechanisms. Methods We analyzed 21 KRAS, NRAS, BRAF, and PI3K wildtype CRC patient-derived xenograft (PDX) models for their anti-EGFR sensitivity. Furthermore, 31 anti-EGFR SR tumors were generated via chronic in vivo treatment with cetuximab. A multi-omics approach was employed to address molecular primary and secondary resistance mechanisms. Gene set enrichment analyses were used to uncover SR pathways. Targeted therapy of SR PDX models was applied to validate selected SR pathways. Results In vivo anti-EGFR SR could be established with high efficiency. Chronic anti-EGFR treatment of CRC PDX tumors induced parallel evolution of multiple resistant lesions with independent molecular SR mechanisms. Mutations in driver genes explained SR development in a subgroup of CRC PDX models, only. Transcriptional reprogramming inducing anti-EGFR SR was discovered as a common mechanism in CRC PDX models frequently leading to RAS signaling pathway activation. We identified cAMP and STAT3 signaling activation, as well as paracrine and autocrine signaling via growth factors as novel anti-EGFR secondary resistance mechanisms. Secondary resistant xenograft tumors could successfully be treated by addressing identified transcriptional changes by tailored targeted therapies. Conclusions Our study demonstrates that SR PDX tumors provide a unique platform to study molecular SR mechanisms and allow testing of multiple treatments for efficient targeting of SR mechanisms, not possible in the patient. Importantly, it suggests that the development of anti-EGFR tolerant cells via transcriptional reprogramming as a cause of anti-EGFR SR in CRC is likely more prevalent than previously anticipated. It emphasizes the need for analyses of SR tumor tissues at a multi-omics level for a comprehensive molecular understanding of anti-EGFR SR in CRC.

Forkhead box A1 (FOXA1) is a pioneer factor that facilitates chromatin binding and function of lineage-specific and oncogenic transcription factors. Hyperactive FOXA1 signaling due to gene amplification or overexpression has been reported in estrogen receptorpositive (ER⁺) endocrine-resistant metastatic breast cancer. However, the molecular mechanisms by which FOXA1 up-regulation promotes these processes and the key downstream targets of the FOXA1 oncogenic network remain elusive. Here, we demonstrate that FOXA1 overexpression in ER⁺ breast cancer cells drives genome-wide enhancer reprogramming to activate prometastatic transcriptional programs. Up-regulated FOXA1 employs superenhancers (SEs) to synchronize transcriptional reprogramming in endocrine-resistant breast cancer cells, reflecting an early embryonic development process. We identify the hypoxia-inducible transcription factor hypoxiainducible factor-2α (HIF-2α) as the top high FOXA1-induced SE target, mediating the impact of high FOXA1 in activating prometastatic gene sets and pathways associated with poor clinical outcome. Using clinical ER⁺/HER2⁻ metastatic breast cancer datasets, we show that the aberrant FOXA1/HIF-2α transcriptional axis is largely nonconcurrent with the ESR1 mutations, suggesting different mechanisms of endocrine resistance and treatment strategies. We further demonstrate the selective efficacy of an HIF-2α antagonist, currently in clinical trials for advanced kidney cancer and recurrent glioblastoma, in reducing the clonogenicity, migration, and invasion of endocrine-resistant breast cancer cells expressing high FOXA1. Our study has uncovered high FOXA1-induced enhancer reprogramming and HIF-2α–dependent transcriptional programs as vulnerable targets for treating endocrine-resistant and metastatic breast cancer.

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.

932 I. 932 II. 933 III. 934 IV. 938 V. 941 943 References 943 SUMMARY: Next to numerous abiotic stresses, plants are constantly exposed to a variety of pathogens within their environment. Thus, their ability to survive and prosper during the course of evolution was strongly dependent on adapting efficient strategies to perceive and to respond to such potential threats. It is therefore not surprising that modern plants have a highly sophisticated immune repertoire consisting of diverse signal perception and intracellular signaling pathways. This signaling network is intricate and deeply interconnected, probably reflecting the diverse lifestyles and infection strategies used by the multitude of invading phytopathogens. Moreover it allows signal communication between developmental and defense programs thereby ensuring that plant growth and fitness are not significantly retarded. How plants integrate and prioritize the incoming signals and how this information is transduced to enable appropriate immune responses is currently a major research area. An important finding has been that pathogen‐triggered cellular responses involve massive transcriptional reprogramming within the host. Additional key observations emerging from such studies are that transcription factors (TFs) are often sites of signal convergence and that signal‐regulated TFs act in concert with other context‐specific TFs and transcriptional co‐regulators to establish sensory transcription regulatory networks required for plant immunity.

Plant defenses induced by salicylic acid (SA) are vital for resistance against biotrophic pathogens. In basal and receptor-triggered immunity, SA accumulation is promoted by Enhanced Disease Susceptibility1 with its co-regulator Phytoalexin Deficient4 (EDS1/PAD4). Current models position EDS1/PAD4 upstream of SA but their functional relationship remains unclear. In a genetic and transcriptomic analysis of Arabidopsis autoimmunity caused by constitutive or conditional EDS1/PAD4 overexpression, intrinsic EDS1/PAD4 signaling properties and their relation to SA were uncovered. A core EDS1/PAD4 pathway works in parallel with SA in basal and effector-triggered bacterial immunity. It protects against disabled SA-regulated gene expression and pathogen resistance, and is distinct from a known SA-compensatory route involving MAPK signaling. Results help to explain previously identified EDS1/PAD4 regulated SA-dependent and SA-independent gene expression sectors. Plants have evolved an alternative route for preserving SA-regulated defenses against pathogen or genetic perturbations. In a proposed signaling framework, EDS1 with PAD4, besides promoting SA biosynthesis, maintains important SA-related resistance programs, thereby increasing robustness of the innate immune system.

Sessile plants are exposed throughout their existence to environmental abiotic and biotic stress factors, such as cold, heat, salinity, drought, dehydration, submergence, waterlogging, and pathogen infection. Chromatin organization affects genome stability, and its dynamics are crucial in plant stress responses. Chromatin dynamics are epigenetically regulated and are required for stress-induced transcriptional regulation or reprogramming. Epigenetic regulators facilitate the phenotypic plasticity of development and the survival and reproduction of plants in unfavorable environments, and they are highly diversified, including histone and DNA modifiers, histone variants, chromatin remodelers, and regulatory non-coding RNAs. They contribute to chromatin modifications, remodeling and dynamics, and constitute a multilayered and multifaceted circuitry for sophisticated and robust epigenetic regulation of plant stress responses. However, this complicated epigenetic regulatory circuitry creates challenges for elucidating the common or differential roles of chromatin modifications for transcriptional regulation or reprogramming in different plant stress responses. Particularly, interacting chromatin modifications and heritable stress memories are difficult to identify in the aspect of chromatin-based epigenetic regulation of transcriptional reprogramming and memory. Therefore, this review discusses the recent updates from the three perspectives—stress specificity or dependence of transcriptional reprogramming, the interplay of chromatin modifications, and transcriptional stress memory in plants. This helps solidify our knowledge on chromatin-based transcriptional reprogramming for plant stress response and memory.

The phytohormone salicylic acid (SA) is a small phenolic compound that regulates diverse physiological processes, in particular plant resistance against pathogens. Understanding SA-mediated signaling has been a major focus of plant research. Pathogen-induced SA is mainly synthesized via the isochorismate pathway in chloroplasts, with ICS1 (ISOCHORISMATE SYNTHASE 1) being a critical enzyme. Calcium signaling regulates activities of a subset of transcription factors thereby activating nuclear ICS1 expression. The produced SA triggers extensive transcriptional reprogramming in which NPR1 (NON-EXPRESSOR of PATHOGENESIS-RELATED GENES 1) functions as the central coactivator of TGA transcription factors. Recently, two alternative but not exclusive models for SA perception mechanisms were proposed. The first model is that NPR1 homologs, NPR3 and NPR4, perceive SA thereby regulating NPR1 protein accumulation. The second model describes that NPR1 itself perceives SA, triggering an NPR1 conformational change thereby activating SA-mediated transcription. Besides the direct SA binding, NPR1 is also regulated by SA-mediated redox changes and phosphorylation. Emerging evidence show that pathogen virulence effectors target SA signaling, further strengthening the importance of SA-mediated immunity.

Seed dormancy and germination are sequential phases, both tightly regulated by environmental and hormonal cues to ensure germination under favorable conditions. While hormonal and transcriptional regulators are well characterized, the epigenetic mechanisms governing these transitions are less understood. We profiled H3K4me3, H3K27me3, and H3K9me3 in the seeds of Arabidopsis thaliana Columbia-0 and Cape Verde Islands, representing shallow and deep dormancy, respectively, at freshly harvested (FH), after-ripened (AR), and germination-stimulated (GS) states. H3K4me3 and H3K9me3 co-localized in euchromatic, transcriptionally active regions, whereas H3K27me3 occupied repressive domains. Histone methylation landscapes were stable from FH to AR but showed a marked H3K9me3 increase from AR to GS in association with the activation of genes related to translation, energy metabolism, and cell division. Co-marking by H3K4me3 and H3K9me3 correlated with highest transcript levels. During dormancy release, AR-repressed genes, including DOG1 , showed targeted reductions in H3K4me3 and H3K9me3 levels. These findings support a plant-specific role of H3K9me3 as an active or permissive chromatin mark promoting transcriptional reprogramming during germination.

Plant grafting is an ancient agricultural practice widely employed in crops such as woody fruit trees, grapes, and vegetables, in order to improve plant performance. Successful grafting requires the interaction of compatible scion and rootstock genotypes. This involves an intricate network of molecular mechanisms operating at the graft junction and associated with the development and the physiology of the scion, ultimately leading to improved agricultural characteristics such as fruit quality and increased tolerance/resistance to abiotic and biotic factors. Bidirectional transfer of molecular signals such as hormones, nutrients, proteins, and nucleic acids from the rootstock to the scion and vice versa have been well documented. In recent years, studies on rootstock-scion interactions have proposed the existence of an epigenetic component in grafting reactions. Epigenetic changes such as DNA methylation, histone modification, and the action of small RNA molecules are known to modulate chromatin architecture, leading to gene expression changes and impacting cellular function. Mobile small RNAs (siRNAs) migrating across the graft union from the rootstock to the scion and vice versa mediate modifications in the DNA methylation pattern of the recipient partner, leading to altered chromatin structure and transcriptional reprogramming. Moreover, graft-induced DNA methylation changes and gene expression shifts in the scion have been associated with variations in graft performance. If these changes are heritable they can lead to stably altered phenotypes and affect important agricultural traits, making grafting an alternative to breeding for the production of superior plants with improved traits. However, most reviews on the molecular mechanisms underlying this process comprise studies related to vegetable grafting. In this review we will provide a comprehensive presentation of the current knowledge on the epigenetic changes and transcriptional reprogramming associated with the rootstock–scion interaction focusing on woody plant species, including the recent findings arising from the employment of advanced—omics technologies as well as transgrafting methodologies and their potential exploitation for generating superior quality grafts in woody species. Furthermore, will discuss graft—induced heritable epigenetic changes leading to novel plant phenotypes and their implication to woody crop improvement for yield, quality, and stress resilience, within the context of climate change.

A long-term treatment of nanoparticles significantly affects various biological processes in plants, including growth and development and stress responses. However, effects of carbon dot (CD) priming on the plant growth and development and the underlying molecular mechanisms have not been completely elucidated. To address this, we herein monitored germination rates of rice seeds with/without CD priming followed by transcriptomic assays using rice roots with/without CD priming. We found that CD priming can promote growth of roots and sprouts in a concentration dependent manner but did not have much impact on germination rates ( t -test, * p  < 0.05, ** p  < 0.01). CD priming exhibited a time dependent effect on transcriptional reprogramming of a subset of genes ( padj  < 0.05, |log 2 (fold change)|> 1), including phytohormone-/development-related transcriptional changes during the seed germination process, which may directly link to CD priming related phenotypic changes of roots. In particular, we provided evidence showing that CD priming can change auxin activities and its spatial distribution in roots, which indicates that CD priming can results in transcriptional changes of some genes ( padj  < 0.05, |log 2 (fold change)|> 1) related to biogenesis and transport of auxin, thereby affecting root growth and development. Thus, this study for the first time provides some insights into how CD priming affects root development through transcriptional reprogramming in rice; especially it provides evidence showing that CD priming can be used as an active regulator of plant growth and development.