NF-κB dynamics determine the stimulus specificity of epigenomic reprogramming in macrophages

The epigenome of macrophages can be reprogrammed by extracellular cues, but the extent to which different stimuli achieve this is unclear. Nuclear factor κB (NF-κB) is a transcription factor that is activated by all pathogen-associated stimuli and can reprogram the epigenome by activating latent enhancers. However, we show that NF-κB does so only in response to a subset of stimuli. This stimulus specificity depends on the temporal dynamics of NF-κB activity, in particular whether it is oscillatory or non-oscillatory. Non-oscillatory NF-κB opens chromatin by sustained disruption of nucleosomal histone–DNA interactions, enabling activation of latent enhancers that modulate expression of immune response genes. Thus, temporal dynamics can determine a transcription factor’s capacity to reprogram the epigenome in a stimulus-specific manner.

Epigenomic atlas in wheat reveals regulatory elements specifying sub-genome divergence

Whole-genome duplication or polyploidy is widespread throughout eukaryotes but is most prevalent in flowering plant lineages. The evolutionary processes following polyploidization, such as genome downsizing, biased fractionation, modulation of gene expression, and epigenomic reprogramming, can profoundly affect genome complexity and generate evolutionarily beneficial genetic diversity. Compared to its diploid and tetraploid progenitors, the allohexaploid common wheat (Triticum aestivum, AABBDD) displays remarkable genome plasticity and broader adaptability, attributed in part to the creation of new genetic diversity following allopolyploidy. How gene copies in the three different subgenomes of wheat are regulated and coordinate molecular responses through combinatorial and dosage-dependent manner is a matter of ongoing research.

Phenotypic plasticity of ER+ breast cancer in the bone microenvironment

SummaryER+ breast cancer exhibits a strong bone-tropism in metastasis. How the bone microenvironment impacts the ER signaling and endocrine therapies remains poorly understood. Here, we discover that the osteogenic niche transiently reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. This is mediated by gap junctions and paracrine FGF/PDGF signaling, which together generate a stable “memory”: cancer cells extracted from bone remain resistant to endocrine therapies for several generations. Using single cell-derived populations (SCPs), we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER+ BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. Our data demonstrates how epigenomic adaptation to the bone microenvironment drives phenotypic plasticity of metastatic seeds and alters their therapeutic responses together with clonal selection, and provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.

Epigenomic reprogramming of repetitive noncoding RNAs and IFN-stimulated genes by mutant KRAS

ABSTRACTRAS genes are the most frequently mutated oncogenes in cancer. However, the effects of oncogenic RAS signaling on the noncoding transcriptome are unclear. We analyzed the transcriptomes of human airway epithelial cells transformed with mutant KRAS to define the landscape of KRAS-regulated noncoding RNAs. We found that oncogenic KRAS upregulates noncoding transcripts throughout the genome, many of which arise from transposable elements. These repetitive noncoding RNAs exhibit differential RNA editing in single cells, are released in extracellular vesicles, and are known targets of KRAB zinc-finger proteins, which are broadly down-regulated in mutant KRAS cells and lung adenocarcinomas. Moreover, mutant KRAS induces IFN-stimulated genes through both epigenetic and RNA-based mechanisms. Our results reveal that mutant KRAS remodels the noncoding transcriptome through epigenomic reprogramming, expanding the scope of genomic elements regulated by this fundamental signaling pathway and revealing how mutant KRAS induces an intrinsic IFN-stimulated gene signature often seen in ADAR-dependent cancers.

Metabolic ink lactate modulates epigenomic landscape: A concerted role of pro-tumor microenvironment and macroenvironment during carcinogenesis

: Tumor heterogeneity is influenced by various factors including genetic, epigenetic and axis of metabolic-epigenomic regulation. In recent, metabolic-epigenomic reprogramming is considered as one of many tumor hallmarks and it appears to be driven by both microenvironment and macroenvironment factors including diet, microbiotas and environmental pressures. Epigenetically, histone lysine residues are altered by various post-translational modifications (PTMs) such as acetylation, acylation, methylation and lactylation. Furthermore, lactylation is suggested as a new form of PTM that uses lactate substrate as a metabolic ink for epigenetic writer enzyme that remodel histone proteins. Therefore, preclinical and clinical attempts are warranted to disrupt pathway of metabolic-epigenomic reprogramming that will turn pro-tumor microenvironment into antitumor microenvironment. This paper highlights the metabolic-epigenomic regulation events including lactylation and its metabolic substrate lactate in tumor microenvironment.

NFκB dynamics determine the stimulus-specificity of epigenomic reprogramming in macrophages

SummaryThe epigenome defines the cell type, but also shows plasticity that enables cells to tune their gene expression potential to the context of extracellular cues. This is evident in immune sentinel cells such as macrophages, which can respond to pathogens and cytokines with phenotypic shifts that are driven by epigenomic reprogramming1. Recent studies indicate that this reprogramming arises from the activity of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), which binds not only to available enhancers but may produce de novo enhancers in previously silent areas of the genome2. Here, we show that NFκB reprograms the macrophage epigenome in a stimulus-specific manner, in response only to a subset of pathogen-derived stimuli. The basis for these surprising differences lies in the stimulus-specific temporal dynamics of NFκB activity. Testing predictions of a mathematical model of nucleosome interactions, we demonstrate through live cell imaging and genetic perturbations that NFκB promotes open chromatin and formation of de novo enhancers most strongly when its activity is non-oscillatory. These de novo enhancers result in the activation of additional response genes. Our study demonstrates that the temporal dynamics of NFκB activity, which encode ligand identity3, can be decoded by the epigenome through de novo enhancer formation. We propose a mechanistic paradigm in which the temporal dynamics of transcription factors are a key determinant of their capacity to control epigenomic reprogramming, thus enabling the formation of stimulus-specific memory in innate immune sentinel cells.