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Atopic dermatitis (AD) is an eczematous, pruritic skin disorder with extensive barrier dysfunction and elevated interleukin (IL)-4 and IL-13 signatures. The barrier dysfunction correlates with the downregulation of barrier-related molecules such as filaggrin (FLG), loricrin (LOR), and involucrin (IVL). IL-4 and IL-13 potently inhibit the expression of these molecules by activating signal transducer and activator of transcription (STAT)6 and STAT3. In addition to IL-4 and IL-13, IL-22 and IL-17A are probably involved in the barrier dysfunction by inhibiting the expression of these barrier-related molecules. In contrast, natural or medicinal ligands for aryl hydrocarbon receptor (AHR) are potent upregulators of FLG, LOR, and IVL expression. As IL-4, IL-13, IL-22, and IL-17A are all capable of inducing oxidative stress, antioxidative AHR agonists such as coal tar, glyteer, and tapinarof exert particular therapeutic efficacy for AD. These antioxidative AHR ligands are known to activate an antioxidative transcription factor, nuclear factor E2-related factor 2 (NRF2). This article focuses on the mechanisms by which FLG, LOR, and IVL expression is regulated by IL-4, IL-13, IL-22, and IL-17A. The author also summarizes how AHR and NRF2 dual activators exert their beneficial effects in the treatment of AD.

Intergenic long noncoding RNAs (lincRNAs) regulate gene expression in various tissues. Zhao and colleagues identify 1,524 lincRNA clusters in thymocytes and mature T cell subsets and reveal dynamic and cell-specific patterns of lincRNA expression during T cell differentiation. Although intergenic long noncoding RNAs (lincRNAs) have been linked to gene regulation in various tissues, little is known about lincRNA transcriptomes in the T cell lineages. Here we identified 1,524 lincRNA clusters in 42 T cell samples, from early T cell progenitors to terminally differentiated helper T cell subsets. Our analysis revealed highly dynamic and cell-specific expression patterns for lincRNAs during T cell differentiation. These lincRNAs were located in genomic regions enriched for genes that encode proteins with immunoregulatory functions. Many were bound and regulated by the key transcription factors T-bet, GATA-3, STAT4 and STAT6. We found that the lincRNA LincR- Ccr2 -5′AS, together with GATA-3, was an essential component of a regulatory circuit in gene expression specific to the T H 2 subset of helper T cells and was important for the migration of T H 2 cells.

Transcriptional reprogramming of proliferative melanoma cells into a phenotypically distinct invasive cell subpopulation is a critical event at the origin of metastatic spreading. Here we generate transcriptome, open chromatin and histone modification maps of melanoma cultures; and integrate this data with existing transcriptome and DNA methylation profiles from tumour biopsies to gain insight into the mechanisms underlying this key reprogramming event. This shows thousands of genomic regulatory regions underlying the proliferative and invasive states, identifying SOX10/MITF and AP-1/TEAD as regulators, respectively. Knockdown of TEADs shows a previously unrecognized role in the invasive gene network and establishes a causative link between these transcription factors, cell invasion and sensitivity to MAPK inhibitors. Using regulatory landscapes and in silico analysis, we show that transcriptional reprogramming underlies the distinct cellular states present in melanoma. Furthermore, it reveals an essential role for the TEADs, linking it to clinically relevant mechanisms such as invasion and resistance. The key regulators that allow transition from proliferative to invasive phenotype in melanoma cells have not been identified yet. The authors perform chromatin and transcriptome profiling followed by comprehensive bioinformatics analysis identifying new candidate regulators for two distinct cell states of melanoma.

s Early B cell lymphopoiesis depends on E2A, Ebf1, Pax5 and Ikaros family members. In the present study, we used acute protein degradation in mice to identify direct target genes of these transcription factors in pro-B, small pre-B and immature B cells. E2A, Ebf1 and Pax5 predominantly function as transcriptional activators by inducing open chromatin at their target genes, have largely unique functions and are essential for early B cell maintenance. Ikaros and Aiolos act as dedicated repressors to cooperatively control early B cell development. The surrogate light-chain genes Igll1 and Vpreb1 are directly activated by Ebf1 and Pax5 in pro-B cells and directly repressed by Ikaros and Aiolos in small pre-B cells. Pax5 and E2A contribute to V(D)J recombination by activating Rag1 , Rag2 , Dntt , Irf4 and Irf8 . Similar to Pax5, Ebf1 also represses the cohesin-release factor gene Wapl to mediate prolonged loop extrusion across the Igh locus. In summary, in vivo protein degradation has provided unprecedented insight into the control of early B cell lymphopoiesis by five transcription factors. By use of a degron-mediated acute protein degradation model, Schwickert and colleagues are able to distinguish between direct and indirect gene targets of multiple transcription factors involved in early B cell development.

Aims/hypothesis The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. Methods The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. Results Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db / db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb , which is expressed in immature beta cells. Conclusions/interpretation The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

Abscisic acid (ABA) reduces accumulation of potentially toxic cadmium (Cd) in plants. How the ABA signal is transmitted to modulate Cd uptake remains largely unclear. Here, we report that the basic region/Leu zipper transcription factor ABSCISIC ACID-INSENSITIVE5 (ABI5), a central ABA signaling molecule, is involved in ABA-repressed Cd accumulation in plants by physically interacting with a previously uncharacterized R2R3-type MYB transcription factor, MYB49. Overexpression of the Cd-induced MYB49 gene in Arabidopsis (Arabidopsis thaliana) resulted in a significant increase in Cd accumulation, whereas myb49 knockout plants and plants expressing chimeric repressors of MYB49:ERF-associated amphiphilic repression motif repression domain (SRDX49) exhibited reduced accumulation of Cd. Further investigations revealed that MYB49 positively regulates the expression of the basic helix-loop-helix transcription factors bHLH38 and bHLH101 by directly binding to their promoters, leading to activation of IRON-REGULATED TRANSPORTER1, which encodes a metal transporter involved in Cd uptake. MYB49 also binds to the promoter regions of the heavy metal-associated isoprenylated plant proteins (HIPP22) and HIPP44, resulting in up-regulation of their expression and subsequent Cd accumulation. On the other hand, as a feedback mechanism to control Cd uptake and accumulation in plant cells, Cd-induced ABA up-regulates the expression of ABI5, whose protein product interacts with MYB49 and prevents its binding to the promoters of downstream genes, thereby reducing Cd accumulation. Our results provide new insights into the molecular feedback mechanisms underlying ABA signaling-controlled Cd uptake and accumulation in plants.

The endocycle is a variant cell cycle consisting of successive DNA synthesis and gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo . Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals. In mammals, polyploidy is only seen in liver hepatocytes and in trophoblast giant cells in the placenta. Leone and colleagues now show that ploidy is controlled in an antagonistic fashion by canonical E2F transcriptional activators and atypical E2F7 and E2F8 repressors, through the control of G2/M-associated genes.

Pluripotency can be induced in somatic cells by overexpressing transcription factors, including POU class 5 homeobox 1 (OCT3/4), sex determining region Y-box 2 (SOX2), Krüppel-like factor 4 (KLF4), and myelocytomatosis oncogene (c-MYC). However, some induced pluripotent stem cells (iPSCs) exhibit defective differentiation and inappropriate maintenance of pluripotency features. Here we show that dynamic regulation of human endogenous retroviruses (HERVs) is important in the reprogramming process toward iPSCs, and in re-establishment of differentiation potential. During reprogramming, OCT3/4, SOX2, and KLF4 transiently hyperactivated LTR7s—the long-terminal repeats of HERV type-H (HERV-H)—to levels much higher than in embryonic stem cells by direct occupation of LTR7 sites genome-wide. Knocking down LTR7s or long intergenic non-protein coding RNA, regulator of reprogramming (lincRNA-RoR), a HERV-H–driven long noncoding RNA, early in reprogramming markedly reduced the efficiency of iPSC generation. KLF4 and LTR7 expression decreased to levels comparable with embryonic stem cells once reprogramming was complete, but failure to resuppress KLF4 and LTR7s resulted in defective differentiation. We also observed defective differentiation and LTR7 activation when iPSCs had forced expression of KLF4. However, when aberrantly expressed KLF4 or LTR7s were suppressed in defective iPSCs, normal differentiation was restored. Thus, a major mechanism by which OCT3/4, SOX2, and KLF4 promote human iPSC generation and reestablish potential for differentiation is by dynamically regulating HERV-H LTR7s.

The general transcription factor IID (TFIID) plays a central role in the initiation of RNA polymerase II (Pol II)-dependent transcription by nucleating pre-initiation complex (PIC) assembly at the core promoter. TFIID comprises the TATA-binding protein (TBP) and 13 TBP-associated factors (TAF1–13), which specifically interact with a variety of core promoter DNA sequences. Here we present the structure of human TFIID in complex with TFIIA and core promoter DNA, determined by single-particle cryo-electron microscopy at sub-nanometre resolution. All core promoter elements are contacted by subunits of TFIID, with TAF1 and TAF2 mediating major interactions with the downstream promoter. TFIIA bridges the TBP–TATA complex with lobe B of TFIID. We also present the cryo-electron microscopy reconstruction of a fully assembled human TAF-less PIC. Superposition of common elements between the two structures provides novel insights into the general role of TFIID in promoter recognition, PIC assembly, and transcription initiation. A sub-nanometre resolution cryo-EM structure of human TFIID bound to TFIIA and core promoter DNA and a model of the TFIID-based pre-initiation complex. Promoter-bound TFIID structure This paper describes the interaction of the human general transcription factor IID (TFIID) with core promoter DNA. TFIID has a central role in the initiation of RNA polymerase II dependent transcription by nucleating assembly of the pre-initiation complex (PIC) at the promoter. Eva Nogales and colleagues determine a sub-nanometre resolution cryo-electron microscopy structure of TFIID bound to TFIIA and core promoter DNA. They also present a cryo-electron microscopy reconstruction of a fully assembled human PIC lacking TBP-associated factors (TAFs). By superimposing common elements between the TFIID–TFIIA–promoter structure and the TAF-less PIC structure, they propose a structural model for the complete TFIID-based PIC, and provide insights into the role of TFIID in promoter recognition, PIC assembly, and transcription initiation.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1 – 4 . Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5 – 8 . By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9 , 10 . However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3 , 4 . Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2 , CBFA2T3 , PRDM6 , UTX and OTX2 . CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens , and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES + KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB. Derailed differentiation of human-specific progenitors of the developing cerebellar rhombic lip is the cause of group 4 medulloblastoma, the most common childhood brain tumour.