Biology subjects

Van Lint, C.

Publications and source records attributed to Van Lint, C..

4 recordsLinked to original sources

bioRxiv2021

Implication of the cellular factor CTCF in the regulation of Bovine Leukemia Virus latency and tridimensional chromatin organization

Bovine Leukemia Virus (BLV)-induced tumoral development is a multifactorial phenomenon which remains largely unelucidated. Here, we highlighted the critical role of the cellular CCCTC-binding factor (CTCF) both in the regulation of BLV transcriptional activities and in the deregulation of the tridimensional (3D) chromatin architecture surrounding the BLV integration site. We demonstrated the in vivo recruitment of CTCF to three conserved CTCF binding motifs along the BLV provirus. Next, we showed a critical role for CTCF in delimitating the epigenetic landscape along the BLV provirus as well as to repress the 5Long Terminal Repeat (LTR) promoter activity, thereby contributing to viral latency, while favoring the 3LTR promoter activity. Finally, we demonstrated that BLV integration deregulated host cellular 3D chromatin organization through the formation of abnormal viral/host chromatin loops. Altogether, our results highlight CTCF as a new critical effector of BLV transcriptional regulation and BLV-induced physiopathology.

molecular biology↗

bioRxiv2021

Novel Role of UHRF1 in DNA methylation-mediated repression of latent HIV-1

The multiplicity, heterogeneity and dynamic nature of HIV-1 latency mechanisms are reflected in the current lack of functional cure for HIV-1 and in the various reported ex vivo potencies of latency- reversing agents. Here, we investigated the molecular mechanisms underlying the potency of the DNA methylation inhibitor 5-aza-2-deoxycytidine (5-AzadC) in HIV-1 latency reversal. Doing so, we uncovered specific demethylation CpG signatures induced by 5-AzadC in the HIV-1 promoter. By analyzing the binding modalities to these CpG, we revealed the recruitment of the epigenetic integrator UHRF1 to the HIV-1 promoter. We further demonstrated the role of UHRF1 in DNA methylation- mediated silencing of the latent HIV-1 promoter. As a proof-of-concept to this molecular characterization, we showed that pharmacological downregulation of UHRF1 in ex vivo HIV+ patient cell cultures resulted in potent reactivation of latent HIV-1. Together, we identify UHRF1 as a novel actor in HIV-1 gene silencing and highlight that it constitutes a new molecular target for HIV-1 curative strategies.

microbiology↗

bioRxiv2020

Mass spectrometry and CLIP-seq analysis reveal BCL11b interactions with RNA processing pathways

BCL11b (B-cell lymphoma/leukemia 11B, CTIP2) is a C2H2 zinc-finger transcription regulator and tumor suppressor. BCL11b is involved in lymphomagenesis and in fetal, central nervous system (CNS) and immune system developments. Therefore, it may contribute in congenital disorders and cancers (e.g. leukemia). BCL11b favors persistence of HIV latency in microglia, CNS macrophages. BCL11b contributes to control cell cycle, differentiation and apoptosis in multiple organisms and cell models; however exact mechanisms are unknown. Although BCL11b recruits non-coding RNA and epigenetic enzymes to regulate gene expression, BCL11b-associated ribonucleoprotein complexes are unknown. Here, using immunoprecipitation of BCL11b-binding RNA and proteins (CLIP-seq and quantitative LC-MS/MS mass spectrometry) complemented with systems biology validations, we show that BCL11b interacts with RNA splicing and nonsense-mediated decay proteins, including FUS, SMN1, UPF1 and Drosha, which may contribute in isoform selection of protein-coding RNA isoforms from noncoding-RNAs isoforms (retained introns or nonsense mediated RNA). Interestingly, BCL11b binds to RNA transcripts and proteins encoded by the same genes (FUS, ESWR1, CHD and Tubulin). Our study highlights that BCL11b targets RNA processing and splicing proteins, and RNAs that implicate cell cycle, development, neurodegenerative, and cancer pathways. These findings will help future mechanistic understanding of developmental disorders. IMPORTANCEFirst genome-wide BCL11b-protein and RNA interactome BCL11b interacts with RNA processing and splicing proteins BCL11b interacts with neurodegenerative genes and sarcoma genes BCL11b targets during cell proliferation and disease pathways

developmental biology↗

bioRxiv2020

Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage

HIV-1 latency generates reservoirs that prevent viral eradication by the current therapies. To find strategies toward an HIV cure, detailed understandings of the molecular mechanisms underlying establishment and persistence of the reservoirs are needed. The cellular transcription factor KAP1 is known as a potent repressor of gene transcription. Here we report that KAP1 represses HIV-1 gene expression in myeloid cells including microglial cells, the major reservoir of the central nervous system. Mechanistically, KAP1 interacts and colocalizes with the viral transactivator Tat to promote its degradation via the proteasome pathway and repress HIV-1 gene expression. In myeloid models of latent HIV-1 infection, the depletion of KAP1 increased viral gene elongation and reactivated HIV-1 expression. Bound to the latent HIV-1 promoter, KAP1 associates and cooperates with CTIP2, a key epigenetic silencer of HIV-1 expression in microglial cells. In addition, Tat and CTIP2 compete for KAP1 binding suggesting a dynamic modulation of the KAP1 cellular partners upon HIV-1 infection. Altogether, our results suggest that KAP1 contributes to the establishment and the persistence of HIV-1 latency in myeloid cells.

molecular biology↗