Normalization Using Weighted Negative Second Order Exponential Error Functions (NeONORM) Provides Robustness Against Asymmetries in Comparative Transcriptome Profiles and Avoids False Calls

“…We previously described acute data analysis of ABI arrays (26,49). Briefly, normalization was achieved using the NeONORM method (50). Significance of log2 (fold change) (designated "log2Q") was determined based on a mixture lognormal distribution hypothesis of signal intensities using mixture ANOVA methodology (51).…”

Section: Methodsmentioning

confidence: 99%

Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response

Jacquelin¹,

Mayau²,

Targat³

et al. 2009

J. Clin. Invest.

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331

487

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African green monkeys (AGMs) infected with the AGM type of SIV (SIVagm) do not develop chronic immune activation and AIDS, despite viral loads similar to those detected in humans infected with HIV-1 and rhesus macaques (RMs) infected with the RM type of SIV (SIVmac). Because chronic immune activation drives progressive CD4 + T cell depletion and immune cell dysfunctions, factors that characterize disease progression, we sought to understand the molecular basis of this AGM phenotype. To this end, we longitudinally assessed the gene expression profiles of blood-and lymph node-derived CD4 + cells from AGMs and RMs in response to SIVagm and SIVmac infection, respectively, using a genomic microarray platform. The molecular signature of acute infection was characterized, in both species, by strong upregulation of type I IFN-stimulated genes (ISGs). ISG expression returned to basal levels after postinfection day 28 in AGMs but was sustained in RMs, especially in the lymph node-derived cells. We also found that SIVagm induced IFN-α production by AGM cells in vitro and that low IFN-α levels were sufficient to induce strong ISG responses. In conclusion, SIV infection triggered a rapid and strong IFN-α response in vivo in both AGMs and RMs, with this response being efficiently controlled only in AGMs, possibly as a result of active regulatory mechanisms.

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“…Data quality was determined using a QC procedure (41). Data were normalized using NeONORM with k = 0.02 (42)(43)(44). Subtraction profiling was performed as in refs.…”

Section: Methodsmentioning

confidence: 99%

CTIP2 is a negative regulator of P-TEFb

Cherrier

Douce

Eilebrecht

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

101

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The positive transcription elongation factor b (P-TEFb) is involved in physiological and pathological events including inflammation, cancer, AIDS, and cardiac hypertrophy. The balance between its active and inactive form is tightly controlled to ensure cellular integrity. We report that the transcriptional repressor CTIP2 is a major modulator of P-TEFb activity. CTIP2 copurifies and interacts with an inactive P-TEFb complex containing the 7SK snRNA and HEXIM1. CTIP2 associates directly with HEXIM1 and, via the loop 2 of the 7SK snRNA, with P-TEFb. In this nucleoprotein complex, CTIP2 significantly represses the Cdk9 kinase activity of P-TEFb. Accordingly, we show that CTIP2 inhibits large sets of P-TEFb-and 7SK snRNA-sensitive genes. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Overexpression of the β-myosin heavy chain protein contributes to the pathological cardiac wall thickening. The inactive P-TEFb complex associates with CTIP2 at the MYH7 gene promoter to repress its activity. Taken together, our results strongly suggest that CTIP2 controls P-TEFb function in physiological and pathological conditions. D iscovered in 1995 (1), P-TEFb (CyclinT1/Cdk9) is involved in physiological and pathological transcriptionally regulated events such as cell growth, differentiation, cancer, cardiac hypertrophy, and AIDS (for review, see refs. 2 and 3). It has been suggested to be required for transcription of most RNA polymerase II-dependent genes. However, a recent study suggests that a subset of cellular genes are distinctively sensitive to Cdk9 inhibition (4). P-TEFb is dynamically regulated by both positive and negative regulators. In contrast to Brd4, which is associated with the active form of P-TEFb (5, 6), the 7SK small nuclear RNA (7SK snRNA) and HEXIM1 inhibit Cdk9 activity in the inactive P-TEFb complex (7-10). P-TEFb elongation complexes are crucial for HIV-1 gene transactivation and viral replication. Recently, new P-TEFb complexes containing the HIV-1 Tat protein have been characterized (11, 12), providing evidence for the recruitment of an inactive Tat/P-TEFb complex to the HIV-1 promoter (13). However, defining the diverse nature and functions of the different P-TEFb complexes will require further investigations. The cellular protein CTIP2 (Bcl11b) has been highlighted as a key transcription factor for thymocyte (14,15) and neuron development (16), odontogenesis (17), cancer evolution (18), and HIV-1 gene silencing (19). Besides AIDS, hypertrophic cardiomyopathy is a well-described P-TEFb-dependent pathology (for review, see refs. 20 and 21).Here, we report that CTIP2 represses P-TEFb function as part of an inactive P-TEFb complex. In hearts of hypertrophic cardiomyopathic mice, CTIP2 controls P-TEFb-sensitive pathways involved in the establishment of this pathology. Together with the inactive P-TEFb complex, CTIP2 associates with the β-myosin heavy chain promoter to repress its activity. Thereby, CTIP2 might contrib...

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Normalization Using Weighted Negative Second Order Exponential Error Functions (NeONORM) Provides Robustness Against Asymmetries in Comparative Transcriptome Profiles and Avoids False Calls

Cited by 29 publications

References 34 publications

Protection against Streptococcus pneumoniae serotype 1 acute infection shows a signature of Th17- and IFN-γ-mediated immunity

Protection against Streptococcus pneumoniae serotype 1 acute infection shows a signature of Th17- and IFN-γ-mediated immunity

Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response

CTIP2 is a negative regulator of P-TEFb

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