Biology subjects

Monziani, A.

Publications and source records attributed to Monziani, A..

4 recordsLinked to original sources

bioRxiv2025

EPB41L4A-AS1 long noncoding RNA acts in both cis- and trans-acting transcriptional regulation and controls nucleolar biology

Mammalian genomes are pervasively transcribed into long noncoding RNAs (lncRNAs), whose functions and modes of action remain poorly understood. EPB41L4A-AS1 is an evolutionary conserved, broadly and highly expressed lncRNA that produces the H/ACA snoRNA SNORA13 from one of its introns. We studied the consequences of EPB41L4A-AS1 perturbation in breast cancer cells and found that it acts both in cis, to enhance transcription of the proximal EPB41L4A gene and additional genes in its two flanking topologically associated domains, and in trans by broadly regulating gene expression, including expression of snoRNAs, transcription of genes involved in nucleolar biology and the distribution of nucleolar proteins. These effects are phenocopied by the loss of SUB1, an interactor of EPB41L4A-AS1, and are observed following transient perturbations of EPB41L4A-AS1 that do not affect steady-state SNORA13 levels or the rRNA modification it helps install. Exogenous expression of the full-length EPB41L4A-AS1 locus but not SNORA13 expression can rescue the trans-acting transcriptional effects of its perturbation. The EPB41L4A-AS1 gene is thus a versatile locus producing RNA molecules acting on multiple levels for key cellular functions.

molecular biology↗

bioRxiv2025

BAHCC1 promotes gene expression in neuronal cells by antagonizing SIN3A-HDAC1

Chromatin modifications play a key role in regulating gene expression during development and adult physiology. Histone acetylation, particularly H3K27ac, is associated with increased activity of gene regulatory elements such as enhancers and promoters. However, the regulation of the machinery that write, read, and erase this modification remains poorly understood. In particular, the SIN3A-HDAC1 complex possesses histone deacetylase activity, yet it commonly resides at active regulatory regions. Here, we study BAHCC1, a large chromatin-associated protein essential for viability, and recently reported to play a largely repressive role. We show that in neuronal lineage cells, BAHCC1 is mainly associated with regulatory elements marked with H3K27ac. BAHCC1 interacts and co-occupies shared genomic regions with the SIN3A scaffold protein, and its perturbations lead to altered acetylation and expression of proximal genes in a neuronal cell line and primary cortical neurons. The regulated genes are enriched for those functioning in neurogenesis and cell migration, and primary cortical neurons with reduced Bahcc1 expression display impaired neurite outgrowth. We thus propose a model in which BAHCC1 antagonizes SIN3A histone deacetylation and positively regulates the expression of genes that are important for growth and migration-related processes in the neuronal lineage.

molecular biology↗

bioRxiv2021

Defective linear and circular RNAs biogenesis in Huntington's disease: CAG repeat expansion hijacks neuronal splicing

Alternative splicing (AS) appears to be altered in Huntingtons disease (HD), but its significance for early, pre-symptomatic disease stages has not been inspected. Here, taking advantage of Htt CAG knock-in mouse in vitro and in vivo models, we demonstrate a strong correlation between Htt CAG repeat length and increased aberrant linear AS, specifically affecting neural progenitors and, in vivo, the striatum prior to overt behavioral phenotypes stages. Remarkably, expanded Htt CAG repeats reflect on a previously neglected, global impairment of back-splicing, leading to decreased circular RNAs production in neural progenitors. Though the mechanisms of this dysregulation remain uncertain, our study unveils network of transcriptionally altered micro-RNAs and RNA-binding proteins (CELF, hnRNPS, PTBP, SRSF) which, in turn, might influence the AS machinery, primarily in neural cells. We suggest that this unbalanced expression of linear and circular RNAs might result in altered neural fitness, contributing to HD striatal vulnerability.

genetics↗

bioRxiv2021

Functional dynamic genetic effects on gene regulation are specific to particular cell types and environmental conditions

Genetic effects on gene expression and splicing can be modulated by cellular and environmental factors; yet interactions between genotypes, cell type and treatment have not been comprehensively studied together. We used an induced pluripotent stem cell system to study multiple cell types derived from the same individuals and exposed them to a large panel of treatments. Cellular responses involved different genes and pathways for gene expression and splicing processes, and were also highly variable across cell types and treatments. For thousands of genes, we identified variable allelic expression across contexts, and characterized different types of gene-environment interactions. Many of these GxE genes are associated with complex traits. We characterized promoter functional and evolutionary features that distinguish genes with elevated allelic imbalance mean and variance. More than 47% of the genes with dynamic regulatory interactions were missed by GTEx, but we identified them using a suitable allelic imbalance study design. This indicates the importance of exploring multiple treatments to reveal previously unrecognized regulatory loci that may be important for disease.

genomics↗