SUMMARY Nonsense-mediated decay (NMD) degrades both normal and aberrant transcripts harboring stop codons in particular contexts. Mutations that perturb NMD cause neurological disorders in humans, suggesting that NMD has roles in the brain. Here, we identify a brain-specific microRNA—miR-128—that represses NMD and thereby controls batteries of transcripts in neural cells. miR-128 represses NMD by targeting the RNA helicase UPF1 and the exon-junction complex core component MLN51. The ability of miR-128 to regulate NMD is a conserved response occuring in frogs, chickens, and mammals. miR-128 levels are dramatically increased in differentiating neuronal cells and during brain development, leading to repressed NMD and upregulation of mRNAs normally targeted for decay by NMD; overrepresented are those encoding proteins controlling neuron development and function. Together, these results suggest the existence of a conserved RNA circuit linking the microRNA and NMD pathways that induces cell type-specific transcripts during development.

IntroductionMultiple myeloma (MM) or plasma cell myeloma is characterized by latent accumulation of secretory plasma cells with a low proliferative index and an extended life span in the bone marrow. 1 The second most prevalent hematologic cancer after non-Hodgkin lymphoma, multiple myeloma accounts for 10% of all hematologic cancers and approximately 2% of all cancer deaths. Conventional therapy for multiple myeloma involves combinations of vincristine, carmustine (bischloroethylnitrosourea), melphalan, cyclophosphamide, doxorubicin (Adriamycin), and prednisone or dexamethasone. 2 Patients younger than 65 years are usually given high-dose melphalan with autologous stem cell support, and older patients or those who cannot tolerate such intensive treatment are given standard-dose oral melphalan and dexamethasone. Shortcomings of these treatments are low remission rates (about 5%), short survival times (median, 30-36 months), and the development of drug resistance. 3,4 Chemoresistance remains a major therapeutic challenge in MM. The precise mechanism underlying chemoresistance in multiple myeloma is not clear, but one of the main contributors to both chemoresistance and pathogenesis is thought to be activation of NF-B and STAT3 and dysregulation of apoptosis. [4][5][6][7][8] Overexpression of antiapoptotic molecules has been linked to chemoresistance in MM; in one study, expression of the antiapoptotic protein Bcl-xL correlated with chemoresistance, with chemoresponse rates of 83% to 87% among non-Bcl-xL-expressing cases but only 20% to 31% among Bcl-xL-expressing cases. 9 Chemoresistance in several types of cancer has been linked to activation of NF-B, a transcription factor with central roles in the regulation of cell growth, survival, angiogenesis, cell adhesion, and apoptosis. 10 Progression and chemoresistance are also thought to involve interleukin 6 (IL-6), expression of which is induced by NF-B, through its regulation of the growth and survival of tumor cells. 11,12 IL-6 leads to constitutive activation of STAT3, which in turn results in expression of high levels of Bcl-xL. 6 Bcl-2 overexpression, another important characteristic of many multiple myeloma cell lines, 13 can rescue cells from glucocorticoid-induced apoptosis. 4 Cell lines resistant to doxorubicin (eg, RPMI 8226-Dox-40) have been shown to overexpress Bcl-xL. 9 Thus, both constitutive activation of NF-B and STAT3 play an important role in chemoresistance, and inhibition of NF-B and STAT3 may overcome this chemoresistance.The use of natural agents may be able to overcome resistance without some of the debilitating side effects of conventional chemotherapy. One such agent is resveratrol, a polyphenol (trans-3, The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on March 22, 2019. by guest www.bloodjournal.org From 4Ј, 5-trihydroxystilbene) abundant in red grape...

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How Sertoli-specific expression is initiated is poorly understood. Here, we address this issue using the proximal promoter (Pp) from the Rhox5 homeobox gene. Its Sertoli cell-specific expression is achieved, in part, through a negative regulatory element that inhibits Pp transcription in non-Sertoli cell lines. Complementing this negative regulation is positive regulation conferred by four androgen-response elements (AREs) that interact with the androgen receptor (AR), a nuclear hormone receptor expressed at high levels in Sertoli cells. A third control mechanism is provided by a consensus GATA-binding site that is crucial for Pp transcription both in vitro and in vivo. Several lines of evidence suggested that GATA factors and AR act cooperatively to activate Pp transcription: (i) the GATA-binding site crucial for Pp transcription is in close proximity to two of the AREs, (ii) GATA and AR form a complex with the Pp in vitro, (iii) overexpression of GATA factors rescued expression from mutant Pp constructs harboring defective AREs, and (iv) incubation of a Sertoli cell line with testosterone triggered corecruitment of AR and GATA4 to the Pp. Collectively, our results suggest that the Rhox5 gene achieves Sertoli cell-specific transcription using a combinatorial strategy involving negative and cooperative positive regulation.

Histone H1 is an abundant and essential component of chromatin whose precise role in regulating gene expression is poorly understood. Here, we report that a major target of H1-mediated regulation in embryonic stem (ES) cells is the X-linked Rhox homeobox gene cluster. To address the underlying mechanism, we examined the founding member of the Rhox gene cluster-Rhox5-and found that its distal promoter (Pd) loses H1, undergoes demethylation, and is transcriptionally activated in response to loss of H1 genes in ES cells. Demethylation of the Pd is required for its transcriptional induction and we identified a single cytosine in the Pd that, when methylated, is sufficient to inhibit Pd transcription. Methylation of this single cytosine prevents the Pd from binding GA-binding protein (GABP), a transcription factor essential for Pd transcription. Thus, H1 silences Rhox5 transcription by promoting methylation of one of its promoters, a mechanism likely to extend to other H1-regulated Rhox genes, based on analysis of ES cells lacking DNA methyltransferases. The Rhox cluster genes targeted for H1-mediated transcriptional repression are also subject to another DNA methylation-regulated process: Xp imprinting. Remarkably, we found that only H1-regulated Rhox genes are imprinted, not those immune to H1-mediated repression. Together, our results indicate that the Rhox gene cluster is a major target of H1-mediated transcriptional repression in ES cells and that H1 is a candidate to have a role in Xp imprinting.