Biology subjects

Heurteau, A.

Publications and source records attributed to Heurteau, A..

3 recordsLinked to original sources

bioRxiv2025

Nuclear exosome targeting complexes modulate cohesin binding and enhancer-promoter interactions in 3D

Three-dimensional long-range contacts between enhancers and promoters are thought to be largely determined by loop extrusion driven by the cohesin complex and insulator factors. However, recent evidence also suggests a role for noncoding RNAs (ncRNAs), such as enhancer-associated RNAs (eRNAs) and promoter upstream transcripts (PROMPTs), in shaping enhancer-promoter connectivity. While nuclear RNA exosome, together with targeting complexes, PAXT and NEXT, control the decay of ncRNAs, it has not yet been determined whether these complexes regulate 3D contacts. Chromatin recruitment maps of ZCCHC8 (NEXT), ZFC3H1 (PAXT) and MTR4 helicase revealed that these factors that associate with sites of enhancer-promoter interactions. Depletion of NEXT, PAXT or MTR4 induced the accumulation of ncRNAs, notably enhancer-associated RNAs (eRNAs) and promoter upstream transcripts (PROMPTs). Strikingly, this further increased cohesin levels at sites accumulating ncRNAs. Chromatin conformation capture analysis revealed that MTR4 modulates the 3D long-range contacts between enhancers with their distant TSS targets. Upon loss of MTR4, contacts at anchor points increase while intraloop contacts decrease, suggesting that MTR4 facilitates loop extrusion. These data highlight a key interplay between cohesin-mediated enhancer-promoter interactions and the regulation of ncRNAs by nuclear RNA exosome that is consistent with a role for RNA in genome folding.

molecular biology↗

bioRxiv2020

The histone variant macroH2A1.1 regulates gene expression by direct association with their transcription start site.

The histone variant macroH2A1.1 (mH2A1.1) plays a role in cancer development and metastasis-related processes. To determine the underlying molecular mechanisms, we mapped genome-wide localization of endogenous mH2A1.1 in the human breast cancer cell MDA-MB 231. We demonstrate that mH2A1.1 specifically binds to active promoters and enhancers in addition to facultative heterochromatin. Selective knock-down of mH2A1.1 deregulates expression of hundreds of highly active genes. Depending on the chromatin landscape, mH2A1.1 acts through two distinct molecular mechanisms. The first is to limit excessive transcription in a predefined environment and relies on domain recruitment of mH2A1.1 at the promoter and gene body. The second mechanism is specific to RNA Pol II (Pol II) paused genes. It requires recruitment of mH2A1.1 restricted to the TSS of these genes. Moreover, we show that these processes occur in a predefined local 3D genome organization and are largely independent of enhancer-promoter looping. Among the genes activated by mH2A1.1, genes regulating mammary tumor cell migration are mostly dependent on Pol II release for their expression level, unlike other categories of mH2A1.1-regulated genes. We thus identified an intriguing new mode of transcriptional regulation by mH2A1.1 and propose that mH2A1.1 serves as a transcriptional modulator with a potential role in assisting the conversion of promoter-locked RNA polymerase II into a productive and elongated Pol II.

genomics↗

bioRxiv2019

NOTCH assembles a transcriptional repressive complex containing NuRD and PRC1 to repress genes involved in cell proliferation and differentiation.

NOTCH1 is best known as a master regulator of T-cell development with a strong oncogenic potential in developing T-cells. Upon induction of Notch, cells go through major transcriptional reprogramming that involves both activation and repression of gene expression. Although much is known about the transcriptional programs activated by Notch, the identity of the genes silenced downstream of Notch signaling and the mechanisms by which Notch down-regulates their expression remain unclear. Here, we show that upon induction of Notch signaling, ICN1-CSL-MAML1 ternary complex assembles a transcriptional Notch Repressive Complex (NRC) containing NuRD and PRC1. Genome wide analysis revealed set of genes bound and transcriptionally repressed by the NRC. Remarkably, among those genes, we found master regulators of cell differentiation and cell proliferation such as PAX5, master B-cell regulator and the DNA-binding transcriptional repressor MAD4. We propose that Notch possesses a dual role as direct activator and repressor by serving as a platform for the recruitment of co-activators and co-repressors on target genes and that both activities are required for Notch nuclear functions.

molecular biology↗