Biology subjects

Gendrel, A.-V.

Publications and source records attributed to Gendrel, A.-V..

3 recordsLinked to original sources

bioRxiv2024

Transcriptional perturbation of LINE-1 elements reveals their cis-regulatory potential

Long interspersed element-1 (LINE-1 or L1) retrotransposons constitute the largest transposable element (TE) family in mammalian genomes and contribute prominently to inter- and intra-individual genetic variation. Although most L1 elements are inactive, some evolutionary younger elements remain intact and genetically competent for transcription and occasionally retrotransposition. Despite being generally more abundant in gene-poor regions, intact or full-length L1s (FL-L1) are also enriched around specific classes of genes and on the eutherian X chromosome. How proximal FL-L1 may affect nearby gene expression remains unclear. In this study, we aim to examine this in a systematic manner using engineered mouse embryonic stem cells (ESCs) where the expression of one representative active L1 subfamily is specifically perturbed. We found that [~]1,024 genes are misregulated following FL-L1 activation and to a lesser extent ([~]81 genes), following their repression. In most cases (68%), misexpressed genes contain an intronic FL-L1 or lie near a FL-L1 (<260 kb). Gene ontology analysis shows that upon L1 activation, up-regulated genes are enriched for neuronal function-related terms, suggesting that some L1 elements may have evolved to control neuronal gene networks. These results illustrate the cis-regulatory impact of FL-L1 elements and suggest a broader role for L1s than originally anticipated.

genomics↗

bioRxiv2021

Locus specific epigenetic modalities of random allelic expression imbalance

Most autosomal genes are thought to be expressed from both alleles, with some notable exceptions, including imprinted genes and genes showing random monoallelic expression (RME). The extent and nature of RME has been the subject of debate. Here we investigate the expression of several candidate RME genes in F1 hybrid mouse cells before and after differentiation, to define how they become persistently, monoallelically expressed. Clonal monoallelic expression was not observed in ESCs, but when we assessed expression status in more than 200 clones of neuronal progenitor cells, we observed high frequencies of monoallelism. We uncovered unforeseen modes of allelic expression that appear to be gene-specific and epigenetically regulated. This non-canonical allelic regulation has important implications for development and disease, including autosomal dominant disorders and opens up novel therapeutic perspectives.

molecular biology↗

bioRxiv2020

Sex of donor cell and reprogramming conditions predict the extent and nature of imprinting defects in mouse iPSCs

Reprogramming of somatic cells into induced Pluripotent Stem Cells (iPSCs) is a major leap towards personalized approaches to disease modelling and cell-replacement therapies. However, we still lack the ability to fully control the epigenetic status of iPSCs, which is a major hurdle for their downstream applications. A sensible indicator for epigenetic fidelity is genomic imprinting, a phenomenon dependent on DNA methylation, which is frequently perturbed in iPSCs by yet unidentified reasons. By using a secondary reprogramming system with murine hybrid donor cells, we conducted a thorough imprinting analysis using IMPLICON in multiple female and male iPSCs generated under different culture conditions. Our results show that imprinting defects are remarkably common in mouse iPSCs causing dysregulation of the typical monoallelic expression of imprinted genes. Interestingly, the nature of imprinting defects depends on the sex of the donor cell and their respective response to culture conditions. Under serum-free conditions, male iPSCs show global hypomethylation at imprinted regions, whereas in serum conditions show focal hypermethylation at specific loci. In contrast, female iPSCs always exhibit hypomethylation defects regardless of culture conditions. These imprinting defects are more severe than the global changes in DNA methylation, highlighting the sensitivity of imprinting loci to current iPSC generation protocols. Our results reveal clear predictors underlying different types of imprinting defects in mouse iPSCs. This knowledge is essential to devise novel reprogramming strategies aiming at generating epigenetically faithful iPSCs.

molecular biology↗