High-Sensitivity Transcriptome Data Structure and Implications for Analysis and Biologic Interpretation

Noth, Sebastian; Brysbaert, Guillaume; Pellay, François-Xavier; Benecke, Arndt

doi:10.1016/s1672-0229(07)60002-3

Cited by 25 publications

(46 citation statements)

References 35 publications

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“…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). Changes in gene expression profiles were considered significant when at least 1 time-point was different from the baseline (P < 0.05).…”

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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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.

Self Cite

331

487

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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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“…For the purposes of investigating the activity of the Shh pathway, data were median centered, log2 transformed, and model adjusted. Interarray and intergroup normalizations were carried out using the NeONORM method described previously (23)(24)(25). Multiple probes for a single gene and cross-reactivity of a single probe to several genes as well as the resolution of probe-ID annotations were accounted for as defined previously (26).…”

Section: Transcriptome Analysismentioning

confidence: 99%

Aldosterone-Producing Adenoma Formation in the Adrenal Cortex Involves Expression of Stem/Progenitor Cell Markers

et al. 2011

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Aldosterone producing adenoma (APA) is the most common form of surgically curable hypertension. To further understand mechanisms involved in APA formation, we investigated the expression of molecules linked to adrenal stem/precursor cells [β-catenin, Sonic hedgehog (Shh), CD56], and nuclear receptors that play key roles in adrenocortical development and function steroidogenic factor 1, dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) in six control adrenal glands and 14 adrenals with APA and compared their expression with that of specific markers of zona glomerulosa (ZG) [CYP11B2, Disabled 2 (Dab2)]. Both Dab2 and CD56 were expressed in ZG. Although Dab2 associates uniquely with differentiated ZG cells and its expression is lost when cells transdifferentiate to zona fasciculata (ZF) cells, CD56 was also expressed in ZF and in aldosterone-producing cell clusters, confirming that these structures possess an intermediate phenotype between ZG and ZF cells. Shh was barely detectable in cells located to the outer part of the ZG in the control adrenal; in contrast, its expression was detected in the entire APA and was dramatically increased in the hyperplastic peritumoral ZG. Transcriptome profiling revealed differential expression of components of Shh signaling pathway in a subgroup of APA. Similarly, Wnt/β-catenin signaling was activated in the majority of APA as well as in the entire peritumoral adrenal cortex; however, no mutation was identified in the CTNNB1 gene that could account for β-catenin activation. Our data suggest that both APA and adjacent ZG present characteristics of stem/precursor cells; the reexpression of genes involved in fetal adrenal development could underlie excessive ZG cell proliferation and APA formation.

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High-Sensitivity Transcriptome Data Structure and Implications for Analysis and Biologic Interpretation

Cited by 25 publications

References 35 publications

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

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

Aldosterone-Producing Adenoma Formation in the Adrenal Cortex Involves Expression of Stem/Progenitor Cell Markers

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