[CTIP2, a multifunctional protein: cellular physiopathology and therapeutic implications]. / CTIP2, une protéine multifonctionnelle - implication en physiopathologie cellulaire et en thérapeutique.

The transcription factor CTIP2 (BCL11B) is a multifunctional protein involved in numerous cell physiological processes. To date, many molecular mechanisms underlying this process have been discovered, which highlighted the importance of the epigenetic regulation of genes and the regulation of the elongation factor P-TEFb. Furthermore studies of the deregulation of CTIP2 showed the association of CTIP2 to numerous pathologies including cancer and cardiac hypertrophy. A better comprehension of the physiopathology of these diseases might lead to the design of therapeutical strategies intending to prevent CTIP2 deregulation. Moreover, CTIP2 and its associated proteins constitute potential targets in strategies aiming to reduce and/or purge HIV-1 cell reservoirs.

HMGA1 recruits CTIP2-repressed P-TEFb to the HIV-1 and cellular target promoters.

Active positive transcription elongation factor b (P-TEFb) is essential for cellular and human immunodeficiency virus type 1 (HIV-1) transcription elongation. CTIP2 represses P-TEFb activity in a complex containing 7SK RNA and HEXIM1. Recently, the inactive 7SK/P-TEFb small nuclear RNP (snRNP) has been detected at the HIV-1 core promoter as well as at the promoters of cellular genes, but a recruiting mechanism still remains unknown to date. Here we show global synergy between CTIP2 and the 7SK-binding chromatin master-regulator HMGA1 in terms of P-TEFb-dependent endogenous and HIV-1 gene expression regulation. While CTIP2 and HMGA1 concordingly repress the expression of cellular 7SK-dependent P-TEFb targets, the simultaneous knock-down of CTIP2 and HMGA1 also results in a boost in Tat-dependent and independent HIV-1 promoter activity. Chromatin immunoprecipitation experiments reveal a significant loss of CTIP2/7SK/P-TEFb snRNP recruitment to cellular gene promoters and the HIV-1 promoter on HMGA1 knock-down. Our findings not only provide insights into a recruiting mechanism for the inactive 7SK/P-TEFb snRNP, but may also contribute to a better understanding of viral latency.

The many lives of CTIP2: from AIDS to cancer and cardiac hypertrophy.

CTIP2 is a key transcriptional regulator involved in numerous physiological functions. Initial works have shown the importance of CTIP2 in the establishment and persistence of HIV latency in microglial cells, the main latent/quiescent viral reservoir in the brain. Recent studies have highlighted the importance of CTIP2 in several other pathologies, such as cardiac hypertrophy and various types of human malignancies. Targeting CTIP2 may therefore constitute a new approach in the treatment of these pathologies.

CTIP2 is a negative regulator of P-TEFb.

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 ß-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.

Achieving a cure for HIV infection: do we have reasons to be optimistic?

The introduction of highly active antiretroviral therapy (HAART) in 1996 has transformed a lethal disease to a chronic pathology with a dramatic decrease in mortality and morbidity of AIDS-related symptoms in infected patients. However, HAART has not allowed the cure of HIV infection, the main obstacle to HIV eradication being the existence of quiescent reservoirs. Several other problems have been encountered with HAART (such as side effects, adherence to medication, emergence of resistance and cost of treatment), and these motivate the search for new ways to treat these patients. Recent advances hold promise for the ultimate cure of HIV infection, which is the topic of this review. Besides these new strategies aiming to eliminate the virus, efforts must be made to improve current HAART. We believe that the cure of HIV infection will not be attained in the short term and that a strategy based on purging the reservoirs has to be associated with an aggressive HAART strategy.

Disruption of the interaction between transcriptional intermediary factor 1{beta} and heterochromatin protein 1 leads to a switch from DNA hyper- to hypomethylation and H3K9 to H3K27 trimethylation on the MEST promoter correlating with gene reactivation.

Here, we identified the imprinted mesoderm-specific transcript (MEST) gene as an endogenous TIF1beta primary target gene and demonstrated that transcriptional intermediary factor (TIF) 1beta, through its interaction with heterochromatin protein (HP) 1, is essential in establishing and maintaining a local heterochromatin-like structure on MEST promoter region characterized by H3K9 trimethylation and hypoacetylation, H4K20 trimethylation, DNA hypermethylation, and enrichment in HP1 that correlates with preferential association to foci of pericentromeric heterochromatin and transcriptional repression. On disruption of the interaction between TIF1beta and HP1, TIF1beta is released from the promoter region, and there is a switch from DNA hypermethylation and histone H3K9 trimethylation to DNA hypomethylation and histone H3K27 trimethylation correlating with rapid reactivation of MEST expression. Interestingly, we provide evidence that the imprinted MEST allele DNA methylation is insensitive to TIF1beta loss of function, whereas the nonimprinted allele is regulated through a distinct TIF1beta-DNA methylation mechanism.