Myoepithelial and oral intracranial myxoid mesenchymal tumor-like neoplasms as diagnostic considerations of the ever-expanding extracranial myxocollagenous tumors harboring FET-CREB fusions.

AIMS: Intracranial myxoid mesenchymal tumors (IMMTs) with fusions between EWSR1/FUS and CREB transcription factors have morphologic overlap with myxoid angiomatoid fibrous histiocytoma (mAFH) and myoepithelial tumor/carcinoma (MET/MEC). We aimed to study the clinicopathologic and genetic spectrum of extracranial IMMT-like tumors and their relationships with mAFH and MET/MEC. METHODS: Twelve extracranial tumors harboring EWSR1/FUS-CREB fusions across different histologic groups were characterized using RNA sequencing, FISH and/or RT-PCR. RESULTS: There were 4 IMMT-like neoplasms, 3 MET/MECs, and 5 mAFHs from the tibia (n=1), oral cavity (n=2), and soft tissues (n=9; 5 in the extremities), harboring EWSR1-ATF1 in 4 cases, FUS-CREM and EWSR1-CREM in 3 each, and EWSR1-CREB1 in 2. Multinodular growth, reticular/cording/trabecular arrangements, myxocollagenous matrix, and lymphocytic infiltrates variably prevailed among the 3 groups. mAFHs were characterized by cells with syncytial cytoplasm. IMMT-like neoplasms and MET/MECs shared cells with distinct boundaries, but only MET/MECs expressed GFAP and/or S100. MUC4 and ALK were expressed in some IMMT-like neoplasms (2/4; 2/4) and mAFH (2/5; 1/5). Pan-TRK reactivity was observed in two IMMT-like neoplasms with upregulated NTRK3 mRNA and one MEC. Local recurrences, typically ≥ 12 months postoperatively, developed in 2/3 IMMT-like neoplasms, 1/2 MET/MECs, and 0/4 mAFHs with follow-up. No definite associations were found between fusion types and histology, immunoprofile or outcome. CONCLUSIONS: We demonstrated the similarities and differences among 3 extracranial myxocollagenous tumor groups sharing EWSR1/FUS-CREB fusions. Oral IMMT-like neoplasms harboring FUS-CREM or EWSR1-ATF1 and FUS-CREM-positive.

Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration.

Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC.

Individual functions of the histone acetyl transferases CBP and p300 in regulating the inflammatory response of synovial fibroblasts.

Chromatin remodeling, and a persistent histone 3 lysine 27 acetylation (H3K27ac) in particular, are associated with a sustained inflammatory response of synovial fibroblasts (SF) in rheumatoid arthritis (RA). Here we investigated individual functions of the writers of H3K27ac marks, the homologues histone acetyl transferases (HAT) CBP and p300, in controlling the constitutive and inflammatory gene expression in RA SF. We applied a silencing strategy, followed by RNA-sequencing and pathway analysis, complemented with the treatment of SF with inhibitors targeting the HAT (C646) or bromo domains (I-CBP) of CBP and p300. We showed that CBP and p300 undertook overlapping and, in particular at gene levels, distinct regulatory functions in SF. p300 is the major HAT for H3K27ac in SF and regulated more diverse pathways than CBP. Whereas both factors regulated genes associated with extracellular matrix remodeling, adhesion and proliferation, p300 specifically controlled developmental genes associated with limb development. Silencing of CBP specifically down regulated the TNF-induced expression of interferon-signature genes. In contrast, silencing of p300 resulted in anti- and pro-inflammatory effects. Integration of data sets derived from RNA-sequencing and chromatin immunoprecipitation sequencing for H3K27ac revealed that changes in gene expression after CBP or p300 silencing could be only partially explained by changes in levels of H3K27ac. Inhibition of CBP/p300 using HAT and bromo domain inhibitors strongly mirrored effects obtained by silencing of p300, including anti- and pro-inflammatory effects, indicating that such inhibitors are not sufficient to be used as anti-inflammatory drugs.

CREB-binding protein (CBP) gene family regulates planarian survival and stem cell differentiation.

In developmental biology, the regulation of stem cell plasticity and differentiation remains an open question. CBP(CREB-binding protein)/p300 is a conserved gene family that functions as a transcriptional co-activator and plays important roles in a wide range of cellular processes, including cell death, the DNA damage response, and tumorigenesis. The acetyl transferase activity of CBPs is particularly important, as histone and non-histone acetylation results in changes in chromatin architecture and protein activity that affect gene expression. Many studies have described the conserved functions of CBP/p300 in stem cell proliferation and differentiation. The planarian Schmidtea mediterranea is an excellent model for the in vivo study of the molecular mechanisms underlying stem cell differentiation during regeneration. However, how this process is regulated genetically and epigenetically is not well-understood yet. We identified 5 distinct Smed-cbp genes in S. mediterranea that show different expression patterns. Functional analyses revealed that Smed-cbp-2 appears to be essential for stem cell maintenance. On the other hand, the silencing of Smed-cbp-3 resulted in the growth of blastemas that were apparently normal, but remained largely unpigmented and undifferentiated. Smed-cbp-3 silencing also affected the differentiation of several cell lineages including neural, epidermal, digestive, and excretory cell types. Finally, we analysed the predicted interactomes of CBP-2 and CBP-3 as an initial step to better understand their functions in planarian stem cell biology. Our results indicate that planarian cbp genes play key roles in stem cell maintenance and differentiation.

3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model in vivo-like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.

Anti-aging Klotho Protects SH-SY5Y Cells Against Amyloid ß1-42 Neurotoxicity: Involvement of Wnt1/pCREB/Nrf2/HO-1 Signaling.

Alzheimer's disease (AD) is considered a prevalent neurological disorder with a neurodegenerative nature in elderly people. Oxidative stress and neuroinflammation due to amyloid ß (Aß) peptides are strongly involved in AD pathogenesis. Klotho is an anti-aging protein with multiple protective effects that its deficiency is involved in development of age-related disorders. In this study, we investigated the beneficial effect of Klotho pretreatment at different concentrations of 0.5, 1, and 2 nM against Aß1-42 toxicity at a concentration of 20 µM in human SH-SY5Y neuroblastoma cells. Our findings showed that Klotho could significantly and partially restore cell viability and decrease reactive oxygen species (known as ROS) and improve superoxide dismutase activity (SOD) in addition to reduction of caspase 3 activity and DNA fragmentation following Aß1-42 challenge. In addition, exogenous Klotho also reduced inflammatory biomarkers consisting of nuclear factor-kB (NF-kB), interleukin-1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) in Aß-exposed cells. Besides, Klotho caused downregulation of Wnt1 level, upregulation of phosphorylated cyclic AMP response element binding (pCREB), and mRNA levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) with no significant alteration of epsilon isoform of protein kinase C (PKCε) after Aß toxicity. In summary, Klotho could alleviate apoptosis, oxidative stress, and inflammation in human neuroblastoma cells after Aß challenge and its beneficial effect is partially exerted through appropriate modulation of Wnt1/pCREB/Nrf2/HO-1 signaling.

A novel miRNA inhibits metastasis of prostate cancer via decreasing CREBBP-mediated histone acetylation.

BACKGROUND: To identify novel miRNAs implicated in prostate cancer metastasis. METHODS: Sixty-five prostate cancer tissues and paired pan-cancer tissues were sequenced. Novel miRNAs were re-analyzed by MIREAP program. Biological functions of miR-N5 were transwell experiment and colony formation. Target genes of miR-N5 were analyzed by bioinformatic analysis. Downstream of target gene was analyzed by The Cancer Genome Atlas (TCGA) and Memorial Sloan Kettering Cancer Center (MSKCC) databases and confirmed by CHIP experiment. RESULTS: We identified a novel miRNA-miR-N5, which was downregulated in PCa cells, PCa tissue, and in the serum of patients with PCa. Knockout of miR-N5 enhanced migration and invasiveness in vitro. miR-N5 specified targeted CREBBP 3'-UTR and inhibited CREBBP expression, which mediated H3K56 acetylation at the promoter of EGFR, ß-catenin and CDH1. CONCLUSION: This study may shed the light on miR-N5 which influences metastasis via histone acetylation.

CREBBP and WDR 24 Identified as Candidate Genes for Quantitative Variation in Red-Brown Plumage Colouration in the Chicken.

Plumage colouration in birds is important for a plethora of reasons, ranging from camouflage, sexual signalling, and species recognition. The genes underlying colour variation have been vital in understanding how genes can affect a phenotype. Multiple genes have been identified that affect plumage variation, but research has principally focused on major-effect genes (such as those causing albinism, barring, and the like), rather than the smaller effect modifier loci that more subtly influence colour. By utilising a domestic × wild advanced intercross with a combination of classical QTL mapping of red colouration as a quantitative trait and a targeted genetical genomics approach, we have identified five separate candidate genes (CREBBP, WDR24, ARL8A, PHLDA3, LAD1) that putatively influence quantitative variation in red-brown colouration in chickens. By treating colour as a quantitative rather than qualitative trait, we have identified both QTL and genes of small effect. Such small effect loci are potentially far more prevalent in wild populations, and can therefore potentially be highly relevant to colour evolution.

CREB transcription in the medial prefrontal cortex regulates the formation of long-term associative recognition memory.

The medial prefrontal cortex (mPFC) is known to be critical for specific forms of long-term recognition memory, however the cellular mechanisms in the mPFC that underpin memory maintenance have not been well characterized. This study examined the importance of phosphorylation of cAMP responsive element binding protein (CREB) in the mPFC for different forms of long-term recognition memory in the rat. Adenoviral transduction of the mPFC with a dominant-negative inhibitor of CREB impaired object-in-place memory following a 6 or 24 h retention delay, but no impairment was observed following delays of 5 min or 3 h. Long-term object temporal order memory and spatial temporal order memory was also impaired. In contrast, there were no impairments in novel object recognition or object location memory. These results establish, for the first time, the importance of CREB phosphorylation within the mPFC for memory of associative and temporal information crucial to recognition.

A CRISPR Interference of CBP and p300 Selectively Induced Synthetic Lethality in Bladder Cancer Cells In Vitro.

The transcriptional coactivator CREB-binding protein (CBP) and p300 are adenoviral E1A-binding proteins involved in various cellular processes, including embryonic development, homeostasis, cell differentiation and transcription activation. Previous study suggested that synthetic lethality between CBP and p300 inhibition in lung and hematopoietic cancers. However, the underlying mechanism of CBP and p300 paralog in bladder cancer remains unknown. In this study, we discovered that combined CBP and p300 inhibition impaired cell proliferation and induced apoptosis of bladder cancer cells and normal bladder urothelial cell via decreasing c-Myc expression. Then, we employed the dCas9-KRAB system, hTERT promoter and hUPII promoter to construct an CRISPR interference system which could specifically repress CBP and p300 expression and cause lethality in bladder cancer cells in vitro. The CRISPR interference system we constructed could specifically inhibit the progression of bladder cancer, providing a novel strategy to fight against bladder cancer.

Crebbp Loss Drives Small Cell Lung Cancer and Increases Sensitivity to HDAC Inhibition.

CREBBP, encoding an acetyltransferase, is among the most frequently mutated genes in small cell lung cancer (SCLC), a deadly neuroendocrine tumor type. We report acceleration of SCLC upon Crebbp inactivation in an autochthonous mouse model. Extending these observations beyond the lung, broad Crebbp deletion in mouse neuroendocrine cells cooperated with Rb1/Trp53 loss to promote neuroendocrine thyroid and pituitary carcinomas. Gene expression analyses showed that Crebbp loss results in reduced expression of tight junction and cell adhesion genes, including Cdh1, across neuroendocrine tumor types, whereas suppression of Cdh1 promoted transformation in SCLC. CDH1 and other adhesion genes exhibited reduced histone acetylation with Crebbp inactivation. Treatment with the histone deacetylase (HDAC) inhibitor Pracinostat increased histone acetylation and restored CDH1 expression. In addition, a subset of Rb1/Trp53/Crebbp-deficient SCLC exhibited exceptional responses to Pracinostat in vivo Thus, CREBBP acts as a potent tumor suppressor in SCLC, and inactivation of CREBBP enhances responses to a targeted therapy.Significance: Our findings demonstrate that CREBBP loss in SCLC reduces histone acetylation and transcription of cellular adhesion genes, while driving tumorigenesis. These effects can be partially restored by HDAC inhibition, which exhibited enhanced effectiveness in Crebbp-deleted tumors. These data provide a rationale for selectively treating CREBBP-mutant SCLC with HDAC inhibitors. Cancer Discov; 8(11); 1422-37. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1333.

Opposing Effects of CREBBP Mutations Govern the Phenotype of Rubinstein-Taybi Syndrome and Adult SHH Medulloblastoma.

Recurrent mutations in chromatin modifiers are specifically prevalent in adolescent or adult patients with Sonic hedgehog-associated medulloblastoma (SHH MB). Here, we report that mutations in the acetyltransferase CREBBP have opposing effects during the development of the cerebellum, the primary site of origin of SHH MB. Our data reveal that loss of Crebbp in cerebellar granule neuron progenitors (GNPs) during embryonic development of mice compromises GNP development, in part by downregulation of brain-derived neurotrophic factor (Bdnf). Interestingly, concomitant cerebellar hypoplasia was also observed in patients with Rubinstein-Taybi syndrome, a congenital disorder caused by germline mutations of CREBBP. By contrast, loss of Crebbp in GNPs during postnatal development synergizes with oncogenic activation of SHH signaling to drive MB growth, thereby explaining the enrichment of somatic CREBBP mutations in SHH MB of adult patients. Together, our data provide insights into time-sensitive consequences of CREBBP mutations and corresponding associations with human diseases.

Multiple functions of CREB-binding protein during postembryonic development: identification of target genes.

BACKGROUND: Juvenile hormones (JH) and ecdysteroids control postembryonic development in insects. They serve as valuable targets for pest management. Hence, understanding the molecular mechanisms of their action is of crucial importance. CREB-binding protein (CBP) is a universal transcriptional co-regulator. It controls the expression of several genes including those from hormone signaling pathways through co-activation of many transcription factors. However, the role of CBP during postembryonic development in insects is not well understood. Therefore, we have studied the role of CBP in postembryonic development in Tribolium, a model coleopteran insect. RESULTS: CBP is ubiquitously expressed in the red flour beetle, Tribolium castaneum. RNA interference (RNAi) mediated knockdown of CBP resulted in a decrease in JH induction of Kr-h1 gene expression in Tribolium larvae and led to a block in their development. Moreover, the injection of CBP double-stranded RNA (dsRNA) showed lethal phenotypes within 8 days of injection. RNA-seq and subsequent differential gene expression analysis identified CBP target genes in Tribolium. Knockdown of CBP caused a decrease in the expression of 1306 genes coding for transcription factors and other proteins associated with growth and development. Depletion of CBP impaired the expression of several JH response genes (e.g., Kr-h1, Hairy, early trypsin) and ecdysone response genes (EcR, E74, E75, and broad complex). Further, GO enrichment analyses of the downregulated genes showed enrichment in different functions including developmental processes, pigmentation, anatomical structure development, regulation of biological and cellular processes, etc. CONCLUSION: These data suggest diverse but crucial roles for CBP during postembryonic development in the coleopteran model insect, Tribolium. It can serve as a target for RNAi mediated pest management of this stored product pest.

Rubinstein-Taybi Syndrome and Epigenetic Alterations.

Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder in humans characterized by growth and psychomotor delay, abnormal gross anatomy, and mild to severe mental retardation (Rubinstein and Taybi, Am J Dis Child 105:588-608, 1963, Hennekam et al., Am J Med Genet Suppl 6:56-64, 1990). RSTS is caused by de novo mutations in epigenetics-associated genes, including the cAMP response element-binding protein (CREBBP), the gene-encoding protein referred to as CBP, and the EP300 gene, which encodes the p300 protein, a CBP homologue. Recent studies of the epigenetic mechanisms underlying cognitive functions in mice provide direct evidence for the involvement of nuclear factors (e.g., CBP) in the control of higher cognitive functions. In fact, a role for CBP in higher cognitive function is suggested by the finding that RSTS is caused by heterozygous mutations at the CBP locus (Petrij et al., Nature 376:348-351, 1995). CBP was demonstrated to possess an intrinsic histone acetyltransferase activity (Ogryzko et al., Cell 87:953-959, 1996) that is required for CREB-mediated gene expression (Korzus et al., Science 279:703-707, 1998). The intrinsic protein acetyltransferase activity in CBP might directly destabilize promoter-bound nucleosomes, facilitating the activation of transcription. Due to the complexity of developmental abnormalities and the possible genetic compensation associated with this congenital disorder, however, it is difficult to establish a direct role for CBP in cognitive function in the adult brain. Although aspects of the clinical presentation in RSTS cases have been extensively studied, a spectrum of symptoms found in RSTS patients can be accessed only after birth, and, thus, prenatal genetic tests for this extremely rare genetic disorder are seldom considered. Even though there has been intensive research on the genetic and epigenetic function of the CREBBP gene in rodents, the etiology of this devastating congenital human disorder is largely unknown.

CREB-binding protein contributes to the regulation of endocrine and developmental pathways in insect hemimetabolan pre-metamorphosis.

BACKGROUND: CREB-binding protein (CBP) is a promiscuous transcriptional co-regulator. In insects, CBP has been studied in the fly Drosophila melanogaster, where it is known as Nejire. Studies in D. melanogaster have revealed that Nejire is involved in the regulation of many pathways during embryo development, especially in anterior/posterior polarity, through Hedgehog and Wingless signaling, and in dorsal/ventral patterning, through TGF-ß signaling. Regarding post-embryonic development, Nejire influences histone acetyl transferase activity on the ecdysone signaling pathway. METHODS AND RESULTS: Functional genomics studies using RNAi have shown that CBP contributes to the regulation of feeding and ecdysis during the pre-metamorphic nymphal instar of the cockroach Blattella germanica and is involved in TGF-ß, ecdysone, and MEKRE93 pathways, contributing to the activation of Kr-h1 and E93 expression. In D. melanogaster, Nejire's involvement in the ecdysone pathway in pre-metamorphic stages is conserved, whereas the TGF-ß pathway has only been described in the embryo. CBP role in ecdysis pathway and in the activation of Kr-h1 and E93 expression is described here for the first time. CONCLUSIONS: Studies in D. melanogaster may have been suggestive that CBP functions in insects are concentrated in the embryo. Results obtained in B. germanica indicate, however, that CBP have diverse and important functions in post-embryonic development and metamorphosis, especially regarding endocrine signaling. GENERAL SIGNIFICANCE: Further research into a higher diversity of models will probably reveal that the multiple post-embryonic roles of CBP observed in B. germanica are general in insects.

Serotonergic regulation of melanocyte conversion: A bioelectrically regulated network for stochastic all-or-none hyperpigmentation.

Experimentally induced depolarization of resting membrane potential in "instructor cells" in Xenopus laevis embryos causes hyperpigmentation in an all-or-none fashion in some tadpoles due to excess proliferation and migration of melanocytes. We showed that this stochastic process involved serotonin signaling, adenosine 3',5'-monophosphate (cAMP), and the transcription factors cAMP response element-binding protein (CREB), Sox10, and Slug. Transcriptional microarray analysis of embryos taken at stage 15 (early neurula) and stage 45 (free-swimming tadpole) revealed changes in the abundance of 45 and 517 transcripts, respectively, between control embryos and embryos exposed to the instructor cell-depolarizing agent ivermectin. Bioinformatic analysis revealed that the human homologs of some of the differentially regulated genes were associated with cancer, consistent with the induced arborization and invasive behavior of converted melanocytes. We identified a physiological circuit that uses serotonergic signaling between instructor cells, melanotrope cells of the pituitary, and melanocytes to control the proliferation, cell shape, and migration properties of the pigment cell pool. To understand the stochasticity and properties of this multiscale signaling system, we applied a computational machine-learning method that iteratively explored network models to reverse-engineer a stochastic dynamic model that recapitulated the frequency of the all-or-none hyperpigmentation phenotype produced in response to various pharmacological and molecular genetic manipulations. This computational approach may provide insight into stochastic cellular decision-making that occurs during normal development and pathological conditions, such as cancer.

Histamine downregulates aquaporin 5 in human nasal epithelial cells.

BACKGROUND: Aquaporin 5 (AQP5) is a water-specific channel protein. It is thought to be a key participant in fluid secretion and a rate-limiting barrier to the secretion seen during allergic inflammation. We sought to determine the effect of histamine on AQP5 expression in human nasal epithelial cells (HNEpC). METHODS: HNEpC cells were cultured with four concentrations of histamine in vitro. The phosphorylation of cyclic adenosine monophosphate-responsive element binding protein (CREB) at serine 133 and the AQP5 protein were measured by using immunocytochemistry and Western blotting. Real-time polymerase chain reaction was used to detect AQP5 messenger ribonucleic acid (mRNA). RESULTS: Concentration-dependent histamine induced-inhibition of CREB phosphorylation at serine 133 in HNEpC cells was observed, and AQP5 mRNA and protein were also downregulated in a concentration-dependent fashion. CONCLUSION: Histamine downregulates AQP5 production in HNEpC cells by inhibiting CREB phosphorylation at serine 133.

Towards a better understanding of cognitive behaviors regulated by gene expression downstream of activity-dependent transcription factors.

In the field of molecular and cellular neuroscience, it is not a trivial task to see the forest for the trees, where numerous, and seemingly independent, molecules often work in concert to control critical steps of synaptic plasticity and signalling. Here, we will first summarize our current knowledge on essential activity-dependent transcription factors (TFs) such as CREB, MEF2, Npas4 and SRF, then examine how various transcription cofactors (TcoFs) also contribute to defining the transcriptional outputs during learning and memory. This review finally attempts a provisory synthesis that sheds new light on some of the emerging principles of neuronal circuit dynamics driven by activity-regulated gene transcription to help better understand the intricate relationship between activity-dependent gene expression and cognitive behavior.

Coactivators p300 and CBP maintain the identity of mouse embryonic stem cells by mediating long-range chromatin structure.

Master transcription factors Oct4, Sox2, and Nanog are required to maintain the pluripotency and self-renewal of embryonic stem cells (ESCs) by regulating a specific transcriptional network. A few other transcription factors have been shown to be important in ESCs by interacting with these master transcription factors; however, little is known about the transcriptional mechanisms regulated by coregulators (coactivators and corepressors). In this study, we examined the function of two highly homologous coactivators, p300 and CREB-binding protein (CBP), in ESCs. We find that these two coactivators play redundant roles in maintaining the undifferentiated state of ESCs. They are recruited by Nanog through physical interaction to Nanog binding loci, mediating the formation of long-range chromatin looping structures, which is essential to maintain ESC-specific gene expression. Further functional studies reveal that the p300/CBP binding looping fragments contain enhancer activities, suggesting that the formation of p300/CBP-mediated looping structures may recruit distal enhancers to create a concentration of factors for the transcription activation of genes that are involved in self-renewal and pluripotency. Overall, these results provide a total new insight into the transcriptional regulation mechanism of coactivators p300 and CBP in ESCs, which is important in maintaining self-renewal and pluripotency, by mediating the formation of higher order chromosome structures.

Epigenetic mechanisms of Rubinstein-Taybi syndrome.

Rubinstein-Taybi syndrome (RTS) is an incurable genetic disorder with combination of mental retardation and physical features including broad thumbs and toes, craniofacial abnormalities, and growth deficiency. While the autosomal dominant mode of transmission is limitedly known, the majority of cases are attributable to de novo mutations in RTS. The first identified gene associated with RTS is CREB-binding protein (CREBBP/CBP). Alterations of the epigenetic 'histone code' due to dysfunction of the CBP histone acetyltransferase activity deregulate gene transcriptions that are prominently linked to RTS pathogenesis. In this review, we discuss how CBP mutation contributes to modifications of histone and how histone deacetylase inhibitors are therapeutically applicable to epigenetic conditioning in RTS. Since most genetic mutations are irreversible and therapeutic approaches are limited, therapeutic targeting of reversible epigenetic components altered in RTS may be an ideal strategy. Expeditious further study on the role of the epigenetic mechanisms in RTS is encouraged to identify novel epigenetic markers and therapeutic targets to treat RTS.