Noncoding RNAs (ncRNAs) direct a remarkable number of diverse functions in development and disease through their regulation of transcription, RNA processing and translation. Leading the charge in the ...RNA revolution is a class of ncRNAs that are synthesized at active enhancers, called enhancer RNAs (eRNAs). Here, we review recent insights into the biogenesis of eRNAs and the mechanisms underlying their multifaceted functions and consider how these findings could inform future investigations into enhancer transcription and eRNA function.
Since its discovery as a skeletal muscle-specific transcription factor able to reprogram somatic cells into differentiated myofibers, MyoD has provided an instructive model to understand how ...transcription factors regulate gene expression. Reciprocally, studies of other transcriptional regulators have provided testable hypotheses to further understand how MyoD activates transcription. Using MyoD as a reference, in this review, we discuss the similarities and differences in the regulatory mechanisms employed by tissue-specific transcription factors to access DNA and regulate gene expression by cooperatively shaping the chromatin landscape within the context of cellular differentiation.
In 1987, Davis, Weintraub, and Lassar reported that MyoD expression converted fibroblasts into myoblasts, opening the field of cell reprogramming. In this review, we use the lessons learned from MyoD to discuss how transcription factors access DNA to regulate gene expression by cooperatively shaping the chromatin landscape.
For many years, stem cell metabolism was viewed as a byproduct of cell fate status rather than an active regulatory mechanism; however, there is now a growing appreciation that metabolic pathways ...influence epigenetic changes associated with lineage commitment, specification, and self-renewal. Here we review how metabolites generated during glycolytic and oxidative processes are utilized in enzymatic reactions leading to epigenetic modifications and transcriptional regulation. We discuss how “metabolic reprogramming” contributes to global epigenetic changes in the context of naive and primed pluripotent states, somatic reprogramming, and hematopoietic and skeletal muscle tissue stem cells, and we discuss the implications for regenerative medicine.
Ryall et al. discuss how “metabolic reprogramming” contributes to global epigenetic changes in stem cells, focusing on how metabolites generated during glycolytic and oxidative processes are utilized in enzymatic reactions for epigenetic regulation. Their discussion centers on changes in pluripotent stem cells and hematopoietic and skeletal muscle stem cells.
The discovery of the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway arose from investigations of how cells respond to interferons (IFNs), revealing a paradigm in ...cell signaling conserved from slime molds to mammals. These discoveries revealed mechanisms underlying rapid gene expression mediated by a wide variety of extracellular polypeptides including cytokines, interleukins, and related factors. This knowledge has provided numerous insights into human disease, from immune deficiencies to cancer, and was rapidly translated to new drugs for autoimmune, allergic, and infectious diseases, including COVID-19. Despite these advances, major challenges and opportunities remain.
The JAK/STAT pathway regulates multiple cellular processes across organisms. Molecular details of signaling mechanisms have revealed insights into a range of human diseases.
Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for ...H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers to regulate cell-type-specific gene expression is unclear. In this study, we identify MLL4 (KMT2D) as a major mammalian H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3 (KMT2C). Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining transcription factors (TFs) on active enhancers during differentiation. Deletion of Mll4 markedly decreases H3K4me1/2, H3K27ac, Mediator and Polymerase II levels on enhancers and leads to severe defects in cell-type-specific gene expression and cell differentiation. Together, these findings identify MLL4 as a major mammalian H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. DOI: http://dx.doi.org/10.7554/eLife.01503.001.
The ability to adapt and respond to nutrients is an ancient cellular function, conserved from unicellular to the most complex multicellular organisms, including mammals. Mammals adapt to changes in ...nutritional status through the modulation of tissue-specific metabolic pathways so as to maintain energy homeostasis. At least two proteins are activated in response to reduced nutrient availability: AMP-activated protein kinase (AMPK) and NAD+-dependent deacetylase SIRT1. AMPK functions as a sensor of cellular energy status and as a master regulator of metabolism. When ATP levels decrease, AMPK is activated to boost ATP production and to inhibit ATP usage, thus restoring energy balance. Similarly, SIRT1 is activated in response to changes in the energy status to promote transcription of genes that mediate the metabolic response to stress, starvation, or calorie restriction. Several observations support a model where, in response to stress and reduced nutrients, a metabolic pathway is activated within which AMPK and SIRT1 concordantly function to ensure an appropriate cellular response and adaptation to environmental modifications. In this perspective, we compare and contrast the roles of SIRT1 and AMPK in several metabolic tissues and propose a working model of how the AMPK-SIRT1 axis may be regulated to control functions relevant to organismal physiology and pathophysiology.
Transcription factors and DNA regulatory binding motifs are fundamental components of the gene regulatory network. Here, by using genome-wide binding profiling, we show extensive occupancy of ...transcription factors of myogenesis (MyoD and Myogenin) at extragenic enhancer regions coinciding with RNA synthesis (i.e., eRNA). In particular, multiple regions were transcribed to eRNA within the regulatory region of MYOD1, including previously characterized distal regulatory regions (DRR) and core enhancer (CE). While CERNA enhanced RNA polymerase II (Pol II) occupancy and transcription at MYOD1, DRRRNA acted to activate the downstream myogenic genes. The deployment of transcriptional machinery to appropriate loci is contingent on chromatin accessibility, a rate-limiting step preceding Pol II assembly. By nuclease sensitivity assay, we found that eRNAs regulate genomic access of the transcriptional complex to defined regulatory regions. In conclusion, our data suggest that eRNAs contribute to establishing a cell-type-specific transcriptional circuitry by directing chromatin-remodeling events.
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•Extensive MyoD and MyoG occupancy in the extragenic regions•RNA synthesis at MyoD+/MyoG+ extragenic enhancer sites•Enhancer RNAs (eRNA) enhance gene expression•eRNAs promote chromatin access to RNA polymerase II at defined genomic loci
T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8
T cell antitumor function by restraining T cell senescence and ...functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8
T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155-Phf19-PRC2 as a pivotal axis regulating CD8
T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8
T cell fate.
Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, enhancer of zeste homolog 2 (Ezh2), triggers ...transcriptional repression by catalyzing the addition of methyl groups onto lysine 27 of histone H3 (H3K27me2/3). This action facilitates the binding of other PcG proteins to chromatin for purposes of transcriptional silencing. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 complex with active epigenetic mark (H3K4me3), RNA polymerase II (Pol II), and mRNA production. Ezh1 depletion reduced global Pol II occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, overexpression of wild-type Ezh1 led to premature gene activation and rescued Pol II occupancy defects in Ezh1-depleted cells. Collectively, these findings reveal a role for a PcG complex in promoting mRNA transcription.
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► The majority of Ezh1-occupied genes are devoid of repressed H3K27me3+ chromatin domains ► Ezh1 occupies H3K4me3+ genes ► The majority of genes occupied by Ezh1 are transcriptionally active ► Ezh1 promotes RNA polymerase II elongation genome-wide
Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent ...stem-cell states distinguished by relative CD34 expression: CD34
, with stemness properties (genuine state), and CD34
, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.
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