Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets.

Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial in the metastatic cascade. Among these, super-enhancers (SEs), emerging as new epigenetic regulators, consist of large clusters of regulatory elements that drive the high-level expression of genes essential for the oncogenic process, upon which cancer cells develop a profound dependency. These SE-driven oncogenes play an important role in regulating various facets of metastasis, including the promotion of tumor proliferation in primary and distal metastatic organs, facilitating cellular migration and invasion into the vasculature, triggering epithelial-mesenchymal transition, enhancing cancer stem cell-like properties, circumventing immune detection, and adapting to the heterogeneity of metastatic niches. This heavy reliance on SE-mediated transcription delineates a vulnerable target for therapeutic intervention in cancer cells. In this article, we review current insights into the characteristics, identification methodologies, formation, and activation mechanisms of SEs. We also elaborate the oncogenic roles and regulatory functions of SEs in the context of cancer metastasis. Ultimately, we discuss the potential of SEs as novel therapeutic targets and their implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.

Mechanism of ERBB2 gene overexpression by the formation of super-enhancer with genomic structural abnormalities in lung adenocarcinoma without clinically actionable genetic alterations.

BACKGROUND: In an extensive genomic analysis of lung adenocarcinomas (LUADs), driver mutations have been recognized as potential targets for molecular therapy. However, there remain cases where target genes are not identified. Super-enhancers and structural variants are frequently identified in several hundred loci per case. Despite this, most cancer research has approached the analysis of these data sets separately, without merging and comparing the data, and there are no examples of integrated analysis in LUAD. METHODS: We performed an integrated analysis of super-enhancers and structural variants in a cohort of 174 LUAD cases that lacked clinically actionable genetic alterations. To achieve this, we conducted both WGS and H3K27Ac ChIP-seq analyses using samples with driver gene mutations and those without, allowing for a comprehensive investigation of the potential roles of super-enhancer in LUAD cases. RESULTS: We demonstrate that most genes situated in these overlapped regions were associated with known and previously unknown driver genes and aberrant expression resulting from the formation of super-enhancers accompanied by genomic structural abnormalities. Hi-C and long-read sequencing data further corroborated this insight. When we employed CRISPR-Cas9 to induce structural abnormalities that mimicked cases with outlier ERBB2 gene expression, we observed an elevation in ERBB2 expression. These abnormalities are associated with a higher risk of recurrence after surgery, irrespective of the presence or absence of driver mutations. CONCLUSIONS: Our findings suggest that aberrant gene expression linked to structural polymorphisms can significantly impact personalized cancer treatment by facilitating the identification of driver mutations and prognostic factors, contributing to a more comprehensive understanding of LUAD pathogenesis.

A CTCF-binding site in the Mdm1-Il22-Ifng locus shapes cytokine expression profiles and plays a critical role in early Th1 cell fate specification.

Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.

Super-enhancer interactomes from single cells link clustering and transcription.

Regulation of gene expression hinges on the interplay between enhancers and promoters, traditionally explored through pairwise analyses. Recent advancements in mapping genome folding, like GAM, SPRITE, and multi-contact Hi-C, have uncovered multi-way interactions among super-enhancers (SEs), spanning megabases, yet have not measured their frequency in single cells or the relationship between clustering and transcription. To close this gap, here we used multiplexed imaging to map the 3D positions of 376 SEs across thousands of mammalian nuclei. Notably, our single-cell images reveal that while SE-SE contacts are rare, SEs often form looser associations we termed "communities". These communities, averaging 4-5 SEs, assemble cooperatively under the combined effects of genomic tethers, Pol2 clustering, and nuclear compartmentalization. Larger communities are associated with more frequent and larger transcriptional bursts. Our work provides insights about the SE interactome in single cells that challenge existing hypotheses on SE clustering in the context of transcriptional regulation.

Super-enhancers: drivers of cells' identities and cells' debacles.

Precise spatiotemporal regulations of gene expression are essential for determining cells' fates and functions. Enhancers are cis-acting DNA elements that act as periodic transcriptional thrusters and their activities are cell type specific. Clusters of enhancers, called super-enhancers, are more densely occupied by transcriptional activators than enhancers, driving stronger expression of their target genes, which have prominent roles in establishing and maintaining cellular identities. Here we review the current knowledge on the composition and structure of super-enhancers to understand how they robustly stimulate the expression of cellular identity genes. We also review their involvement in the development of various cell types and both noncancerous and cancerous disorders, implying the therapeutic interest of targeting them to fight against various diseases.

m6A-dependent upregulation of DDX21 by super-enhancer-driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia.

BACKGROUND: Acute myeloid leukaemia (AML) is a haematological malignancy with unfavourable prognosis. Despite the effectiveness of chemotherapy and targeted therapy, relapse or drug resistance remains a major threat to AML patients. N6-methyladenosine (m6A) RNA methylation and super-enhancers (SEs) are extensively involved in the leukaemogenesis of AML. However, the potential relationship between m6A and SEs in AML has not been elaborated. METHODS: Chromatin immunoprecipitation (ChIP) sequencing data from Gene Expression Omnibus (GEO) cohort were analysed to search SE-related genes. The mechanisms of m6 A-binding proteins IGF2BP2 and IGF2BP3 on DDX21 were explored via methylated RNA immunoprecipitation (MeRIP) assays, RNA immunoprecipitation (RIP) assays and luciferase reporter assays. Then we elucidated the roles of DDX21 in AML through functional assays in vitro and in vivo. Finally, co-immunoprecipitation (Co-IP) assays, RNA sequencing and ChIP assays were performed to investigate the downstream mechanisms of DDX21. RESULTS: We identified two SE-associated transcripts IGF2BP2 and IGF2BP3 in AML. High enrichment of H3K27ac, H3K4me1 and BRD4 was observed in IGF2BP2 and IGF2BP3, whose expression were driven by SE machinery. Then IGF2BP2 and IGF2BP3 enhanced the stability of DDX21 mRNA in an m6A-dependent manner. DDX21 was highly expressed in AML patients, which indicated a poor survival. Functionally, knockdown of DDX21 inhibited cell proliferation, promoted cell apoptosis and led to cell cycle arrest. Mechanistically, DDX21 recruited transcription factor YBX1 to cooperatively trigger ULK1 expression. Moreover, silencing of ULK1 could reverse the promoting effects of DDX21 overexpression in AML cells. CONCLUSIONS: Dysregulation of SE-IGF2BP2/IGF2BP3-DDX21 axis facilitated the progression of AML. Our findings provide new insights into the link between SEs and m6A modification, elucidate the regulatory mechanisms of IGF2BP2 and IGF2BP3 on DDX21, and reveal the underlying roles of DDX21 in AML.

Multifaceted roles of cohesin in regulating transcriptional loops.

Cohesin is required for chromatin loop formation. However, its precise role in regulating gene transcription remains largely unknown. We investigated the relationship between cohesin and RNA Polymerase II (RNAPII) using single-molecule mapping and live-cell imaging methods in human cells. Cohesin-mediated transcriptional loops were highly correlated with those of RNAPII and followed the direction of gene transcription. Depleting RAD21, a subunit of cohesin, resulted in the loss of long-range (>100 kb) loops between distal (super-)enhancers and promoters of cell-type-specific genes. By contrast, the short-range (<50 kb) loops were insensitive to RAD21 depletion and connected genes that are mostly housekeeping. This result explains why only a small fraction of genes are affected by the loss of long-range chromatin interactions due to cohesin depletion. Remarkably, RAD21 depletion appeared to up-regulate genes located in early initiation zones (EIZ) of DNA replication, and the EIZ signals were amplified drastically without RAD21. Our results revealed new mechanistic insights of cohesin's multifaceted roles in establishing transcriptional loops, preserving long-range chromatin interactions for cell-specific genes, and maintaining timely order of DNA replication.

Pathogenic role of super-enhancers as potential therapeutic targets in lung cancer.

Lung cancer is still one of the deadliest malignancies today, and most patients with advanced lung cancer pass away from disease progression that is uncontrollable by medications. Super-enhancers (SEs) are large clusters of enhancers in the genome's non-coding sequences that actively trigger transcription. Although SEs have just been identified over the past 10 years, their intricate structure and crucial role in determining cell identity and promoting tumorigenesis and progression are increasingly coming to light. Here, we review the structural composition of SEs, the auto-regulatory circuits, the control mechanisms of downstream genes and pathways, and the characterization of subgroups classified according to SEs in lung cancer. Additionally, we discuss the therapeutic targets, several small-molecule inhibitors, and available treatment options for SEs in lung cancer. Combination therapies have demonstrated considerable advantages in preclinical models, and we anticipate that these drugs will soon enter clinical studies and benefit patients.

Integrative analysis and risk model construction for super­enhancer­related immune genes in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer associated with poor prognosis, and accounts for the majority of RCC-related deaths. The lack of comprehensive diagnostic and prognostic biomarkers has limited further understanding of the pathophysiology of ccRCC. Super-enhancers (SEs) are congregated enhancer clusters that have a key role in tumor processes such as epithelial-mesenchymal transition, metabolic reprogramming, immune escape and resistance to apoptosis. RCC may also be immunogenic and sensitive to immunotherapy. In the present study, an Arraystar human SE-long non-coding RNA (lncRNA) microarray was first employed to profile the differentially expressed SE-lncRNAs and mRNAs in 5 paired ccRCC and peritumoral tissues and to identify SE-related genes. The overlap of these genes with immune genes was then determined to identify SE-related immune genes. A model for predicting clinical prognosis and response to immunotherapy was built following the comprehensive analysis of a ccRCC gene expression dataset from The Cancer Genome Atlas (TCGA) database. The patients from TCGA were divided into high- and low-risk groups based on the median score derived from the risk model, and the Kaplan-Meier survival analysis showed that the low-risk group had a higher survival probability. In addition, according to the receiver operating characteristic curve analysis, the risk model had more advantages than other clinical factors in predicting the overall survival (OS) rate of patients with ccRCC. Using this model, it was demonstrated that the high-risk group had a more robust immune response. Furthermore, 61 potential drugs with half-maximal inhibitory concentration values that differed significantly between the two patient groups were screened to investigate potential drug treatment of ccRCC. In summary, the present study provided a novel index for predicting the survival probability of patients with ccRCC and may provide some insights into the mechanisms through which SE-related immune genes influence the diagnosis, prognosis and potential treatment drugs of ccRCC.

Super-Enhancers and Their Parts: From Prediction Efforts to Pathognomonic Status.

Super-enhancers (SEs) are regions of the genome that play a crucial regulatory role in gene expression by promoting large-scale transcriptional responses in various cell types and tissues. Recent research suggests that alterations in super-enhancer activity can contribute to the development and progression of various disorders. The aim of this research is to explore the multifaceted roles of super-enhancers in gene regulation and their significant implications for understanding and treating complex diseases. Here, we study and summarise the classification of super-enhancer constituents, their possible modes of interaction, and cross-regulation, including super-enhancer RNAs (seRNAs). We try to investigate the opportunity of SE dynamics prediction based on the hierarchy of enhancer single elements (enhancers) and their aggregated action. To further our understanding, we conducted an in silico experiment to compare and differentiate between super-enhancers and locus-control regions (LCRs), shedding light on the enigmatic relationship between LCRs and SEs within the human genome. Particular attention is paid to the classification of specific mechanisms and their diversity, exemplified by various oncological, cardiovascular, and immunological diseases, as well as an overview of several anti-SE therapies. Overall, the work presents a comprehensive analysis of super-enhancers across different diseases, aiming to provide insights into their regulatory roles and may act as a rationale for future clinical interventions targeting these regulatory elements.

Identification of potential pathogenic hepatic super-enhancers regulatory network in high-fat diet induced hyperlipidemia.

Hyperlipidemia (HLP) is a prevalent metabolic disorder and a significant risk factor for cardiovascular disease. According to recent discoveries, super-enhancers (SEs) play a role in the increased expression of genes that encode important regulators of both cellular identity and the progression of diseases. However, the underlying function of SEs in the development of HLP is still unknown. We performed an integrative analysis of data on H3K27ac ChIP-seq and RNA sequencing obtained from liver tissues of mice under a low-fat diet (LFD) and high-fat diet (HFD) from GEO database. The rank ordering of super enhancers algorithm was employed for the computation and identification of SEs. A total of 1,877 and 1,847 SEs were identified in the LFD and HFD groups, respectively. The SE inhibitor JQ1 was able to potently reverse lipid deposition and the increased intracellular triglyceride and total cholesterol induced by oleic acid, indicating that SEs are involved in regulating lipid accumulation. Two hundred seventy-eight were considered as HFD-specific SEs (HSEs). GO and KEGG pathway enrichment analysis of the upregulated HSEs-associated genes revealed that they were mainly involved in lipid metabolic pathway. Four hub genes, namely Cd36, Pex11a, Ech1, and Cidec, were identified in the HSEs-associated protein-protein interaction network, and validated with two other datasets. Finally, we constructed a HSEs-specific regulatory network with Cidec and Cd36 as the core through the prediction and verification of transcription factors. Our study constructed a HSEs-associated regulatory network in the pathogenesis of HLP, providing new ideas for the underlying mechanisms and therapeutic targets of HLP.

Differentiated neuroblastoma cells remain epigenetically poised for de-differentiation to an immature state.

Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for a significant share of childhood cancer deaths. Prior studies utilizing RNA sequencing of bulk tumor populations showed two predominant cell states characterized by high and low expression of neuronal genes. Although cells respond to treatment by altering their gene expression, it is unclear whether this reflects shifting balances of distinct subpopulations or plasticity of individual cells. Using mouse and human neuroblastoma cell lines lacking MYCN amplification, we show that the antigen CD49b (also known as ITGA2) distinguishes these subpopulations. CD49b expression marked proliferative cells with an immature gene expression program, whereas CD49b-negative cells expressed differentiated neuronal marker genes and were non-cycling. Sorted populations spontaneously switched between CD49b expression states in culture, and CD49b-negative cells could generate rapidly growing, CD49b-positive tumors in mice. Although treatment with the chemotherapy drug doxorubicin selectively killed CD49b-positive cells in culture, the CD49b-positive population recovered when treatment was withdrawn. We profiled histone 3 (H3) lysine 27 acetylation (H3K27ac) to identify enhancers and super enhancers that were specifically active in each population and found that CD49b-negative cells maintained the priming H3 lysine 4 methylation (H3K4me1) mark at elements that were active in cells with high expression of CD49b. Improper maintenance of primed enhancer elements might thus underlie cellular plasticity in neuroblastoma, representing potential therapeutic targets for this lethal tumor.

Super-enhancers include classical enhancers and facilitators to fully activate gene expression.

Super-enhancers are compound regulatory elements that control expression of key cell identity genes. They recruit high levels of tissue-specific transcription factors and co-activators such as the Mediator complex and contact target gene promoters with high frequency. Most super-enhancers contain multiple constituent regulatory elements, but it is unclear whether these elements have distinct roles in activating target gene expression. Here, by rebuilding the endogenous multipartite α-globin super-enhancer, we show that it contains bioinformatically equivalent but functionally distinct element types: classical enhancers and facilitator elements. Facilitators have no intrinsic enhancer activity, yet in their absence, classical enhancers are unable to fully upregulate their target genes. Without facilitators, classical enhancers exhibit reduced Mediator recruitment, enhancer RNA transcription, and enhancer-promoter interactions. Facilitators are interchangeable but display functional hierarchy based on their position within a multipartite enhancer. Facilitators thus play an important role in potentiating the activity of classical enhancers and ensuring robust activation of target genes.

Super-enhancer-associated EEPD1 facilitates EMT-mediated metastasis by regulating the PI3K/AKT/mTOR pathway in gastric cancer.

This study focused on exploring the mechanism of the EMT mediated by endonuclease/exonuclease/phosphatase family domain-containing 1 (EEPD1) in gastric cancer metastasis. Through bioinformatics analysis, EEPD1 was found to be a target gene of super enhancers (SEs) in gastric cancer tissues. EEPD1 exhibited higher expression levels in tumor tissues and was associated with poor prognosis. In vitro and in vivo studies have demonstrated that silencing EEPD1 significantly suppressed the proliferation, metastasis, and invasion of gastric cancer cells. Furthermore, EEPD1 knockdown was involved in the regulation of the EMT and suppressed expression of AKT, a downstream component of the PI3K pathway, leading to a reduction in the phosphorylation levels of AKT and its downstream molecule, mTOR. These results showed the potential of EEPD1 as a prognostic indicator and therapeutic target in gastric cancer.

Super-enhancer driven SOX2 promotes tumor formation by chromatin re-organization in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with a high incidence in Southern China and Southeast Asia. Patients with remote metastasis and recurrent NPC have poor prognosis. Thus, a better understanding of NPC pathogenesis may identify novel therapies to address the unmet clinical needs. METHODS: H3K27ac ChIP-seq and HiChIP was applied to understand the enhancer landscapes and the chromosome interactions. Whole genome sequencing was conducted to analyze the relationship between genomic variations and epigenetic dysregulation. CRISPRi and JQ1 treatment were used to evaluate the transcriptional regulation of SOX2 SEs. Colony formation assay, survival analysis and in vivo subcutaneous patient-derived xenograft assays were applied to explore the function and clinical relevance of SOX2 in NPC. FINDINGS: We globally mapped the enhancer landscapes and generated NPC enhancer connectomes, linking NPC specific enhancers and SEs. We found five overlapped genes, including SOX2, among super-enhancer regulated genes, survival related genes and NPC essential genes. The mRNA expression of SOX2 was repressed when applying CRISPRi targeting different SOX2 SEs or JQ1 treatment. Next, we identified a genetic variation (Chr3:181422197, G > A) in SOX2 SE which is correlated with higher expression of SOX2 and poor survival. In addition, SOX2 was highly expressed in NPC and is correlated with short survival in patients with NPC. Knock-down of SOX2 suppressed tumor growth in vitro and in vivo. INTERPRETATION: Our study demonstrated the super-enhancer landscape with chromosome interactions and identified super-enhancer driven SOX2 promotes tumorigenesis, suggesting that SOX2 is a potential therapeutic target for patients with NPC. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

A body map of super-enhancers and their function in pig.

Introduction: Super-enhancers (SEs) are clusters of enhancers that act synergistically to drive the high-level expression of genes involved in cell identity and function. Although SEs have been extensively investigated in humans and mice, they have not been well characterized in pigs. Methods: Here, we identified 42,380 SEs in 14 pig tissues using chromatin immunoprecipitation sequencing, and statistics of its overall situation, studied the composition and characteristics of SE, and explored the influence of SEs characteristics on gene expression. Results: We observed that approximately 40% of normal enhancers (NEs) form SEs. Compared to NEs, we found that SEs were more likely to be enriched with an activated enhancer and show activated functions. Interestingly, SEs showed X chromosome depletion and short interspersed nuclear element enrichment, implying that SEs play an important role in sex traits and repeat evolution. Additionally, SE-associated genes exhibited higher expression levels and stronger conservation than NE-associated genes. However, genes with the largest SEs had higher expression levels than those with the smallest SEs, indicating that SE size may influence gene expression. Moreover, we observed a negative correlation between SE gene distance and gene expression, indicating that the proximity of SEs can affect gene activity. Gene ontology enrichment and motif analysis revealed that SEs have strong tissue-specific activity. For example, the CORO2B gene with a brain-specific SE shows strong brain-specific expression, and the phenylalanine hydroxylase gene with liver-specific SEs shows strong liver-specific expression. Discussion: In this study, we illustrated a body map of SEs and explored their functions in pigs, providing information on the composition and tissue-specific patterns of SEs. This study can serve as a valuable resource of gene regulatory and comparative analyses to the scientific community and provides a theoretical reference for genetic control mechanisms of important traits in pigs.

HOXDeRNA activates a cancerous transcription program and super-enhancers genome-wide.

Background: The origin and genesis of highly malignant and heterogenous glioblastoma brain tumors remain unknown. We previously identified an enhancer-associated long non-coding RNA, LINC01116 (named HOXDeRNA here), that is absent in the normal brain but is commonly expressed in malignant glioma. HOXDeRNA has a unique capacity to transform human astrocytes into glioma-like cells. This work aimed to investigate molecular events underlying the genome-wide function of this lncRNA in glial cell fate and transformation. Results: Using a combination of RNA-Seq, ChIRP-Seq, and ChIP-Seq, we now demonstrate that HOXDeRNA binds in trans to the promoters of genes encoding 44 glioma-specific transcription factors distributed throughout the genome and derepresses them by removing the Polycomb repressive complex 2 (PRC2). Among the activated transcription factors are the core neurodevelopmental regulators SOX2, OLIG2, POU3F2, and SALL2. This process requires an RNA quadruplex structure of HOXDeRNA that interacts with EZH2. Moreover, HOXDeRNA-induced astrocyte transformation is accompanied by the activation of multiple oncogenes such as EGFR, PDGFR, BRAF, and miR-21, and glioma-specific super-enhancers enriched for binding sites of glioma master transcription factors SOX2 and OLIG2. Conclusions: Our results demonstrate that HOXDeRNA overrides PRC2 repression of glioma core regulatory circuitry with RNA quadruplex structure. These findings help reconstruct the sequence of events underlying the process of astrocyte transformation and suggest a driving role for HOXDeRNA and a unifying RNA-dependent mechanism of gliomagenesis.

Etiology of super-enhancer reprogramming and activation in cancer.

Super-enhancers are large, densely concentrated swaths of enhancers that regulate genes critical for cell identity. Tumorigenesis is accompanied by changes in the super-enhancer landscape. These aberrant super-enhancers commonly form to activate proto-oncogenes, or other genes upon which cancer cells depend, that initiate tumorigenesis, promote tumor proliferation, and increase the fitness of cancer cells to survive in the tumor microenvironment. These include well-recognized master regulators of proliferation in the setting of cancer, such as the transcription factor MYC which is under the control of numerous super-enhancers gained in cancer compared to normal tissues. This Review will cover the expanding cell-intrinsic and cell-extrinsic etiology of these super-enhancer changes in cancer, including somatic mutations, copy number variation, fusion events, extrachromosomal DNA, and 3D chromatin architecture, as well as those activated by inflammation, extra-cellular signaling, and the tumor microenvironment.

Super-enhancer-driven lncRNA Snhg7 aggravates cardiac hypertrophy via Tbx5/GLS2/ferroptosis axis.

Long non-coding RNAs (lncRNAs) are expressed aberrantly in cardiac disease, but their roles in cardiac hypertrophy are still unknown. Here we sought to identify a specific lncRNA and explore the mechanisms underlying lncRNA functions. Our results revealed that lncRNA Snhg7 was a super-enhancer-driven gene in cardiac hypertrophy by using chromatin immunoprecipitation sequencing (ChIP-seq). We next found that lncRNA Snhg7 induced ferroptosis by interacting with T-box transcription factor 5 (Tbx5), a cardiac transcription factor. Moreover, Tbx5 bound to the promoter of glutaminase 2 (GLS2) and regulated cardiomyocyte ferroptosis activity in cardiac hypertrophy. Importantly, extra-terminal domain inhibitor JQ1 could suppress super-enhancers in cardiac hypertrophy. Inhibition of lncRNA Snhg7 could block the expressions of Tbx5, GLS2 and levels of ferroptosis in cardiomyocytes. Furthermore, we verified that Nkx2-5 as a core transcription factor, directly bound the super-enhancer of itself and lncRNA Snhg7, increasing both of their activation. Collectively, we are the first to identify lncRNA Snhg7 as a novel functional lncRNA in cardiac hypertrophy, might regulate cardiac hypertrophy via ferroptosis. Mechanistically, lncRNA Snhg7 could transcriptionally regulate Tbx5/GLS2/ferroptosis in cardiomyocytes.

Transcription factor condensates and signaling driven transcription.

Transcription Factor (TF) condensates are a heterogenous mix of RNA, DNA, and multiple co-factor proteins capable of modulating the transcriptional response of the cell. The dynamic nature and the spatial location of TF-condensates in the 3D nuclear space is believed to provide a fast response, which is on the same pace as the signaling cascade and yet ever-so-specific in the crowded environment of the nucleus. However, the current understanding of how TF-condensates can achieve these feet so quickly and efficiently is still unclear. In this review, we draw parallels with other protein condensates and share our speculations on how the nucleus uses these TF-condensates to achieve high transcriptional specificity and fidelity. We discuss the various constituents of TF-condensates, their properties, and the known and unknown functions of TF-condensates with a particular focus on steroid signaling-induced transcriptional programs.