Biology subjects

ROHR, O.

Publications and source records attributed to ROHR, O..

4 recordsLinked to original sources

bioRxiv2026

THE HIV-1 SILENCER BCL11B/CTIP2 REGULATES THE TLR3-MEDIATED CELLULAR RESPONSE TO VIRAL INFECTIONS

HIV-1 latency remains a major barrier to viral eradication. The persistence of the latently infected reservoirs results from multifactorial mechanisms controlling gene transcription and cellular responses to viral reactivation. The transcriptional repressor BCL11B/CTIP2 is known to promote the establishment and persistence of the latently infected reservoirs. However, its contribution to the cellular response to viral infection has not been investigated before. Together with HEXIM1, paraspeckles contribute to cellular innate sensing of viral infections and to the production of type I interferons. Paraspeckles are nuclear membrane-less organelles composed of proteins, including SFPQ/PSF and NONO, wrapped around the long non-coding RNA NEAT1. Here, we show that HIV-1 infection promotes a TLR3-mediated CTIP2 overexpression delayed from a transitory NEAT1 overexpression, paraspeckles formation and type I IFN production. In response to this interferon production, CTIP2 is recruited to the NEAT1 promotor together with HEXIM1 and repressive histone marks to inhibit NEAT1 gene expression. The resulting depletion of the paraspeckles abrogated INF production, dampening TLR3 signalling and reinforcing HIV-1 latency. Our results demonstrate CTIP2 as a dual-function regulator that silences HIV-1 transcription and restricts antiviral innate immune response as part of a negative feedback loop limiting the interferon response to viral infection. O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/699245v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@7ab0b0org.highwire.dtl.DTLVardef@e60aa6org.highwire.dtl.DTLVardef@c5564corg.highwire.dtl.DTLVardef@1a4bbe0_HPS_FORMAT_FIGEXP M_FIG C_FIG

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↗