Biology subjects

Mupo, A.

Publications and source records attributed to Mupo, A..

3 recordsLinked to original sources

bioRxiv2023

Stability of Genomic Imprinting and X-Chromosome Inactivation in the Aging Brain

Epigenetic drift is a hallmark of aging that contributes to the irreversible decline in organismal fitness ultimately leading to aging-related diseases. Epigenetic modifications regulate the cellular memory of the epigenetic processes of genomic imprinting and X-chromosome inactivation to ensure monoallelic expression of imprinted and X-linked genes. Whether epigenetic drift affects maintenance of genomic imprinting and X-chromosome inactivation has not been comprehensively studied. Here, we investigate the allele-specific transcriptional and epigenetic signatures of the aging brain, by comparing juvenile and old hybrid mice obtained from C57BL/6J (BL6) & CAST/EiJ (CAST) reciprocal crosses, with an emphasis on the hippocampus (HCP). We confirm that the aged HCP shows an increase of DNA hydroxymethylation, a sign of epigenetic drift, and a typical aging transcriptional signature. Genomic imprinting was found to be largely unaffected with stable parent-of-origin-specific DNA methylation in HCP, but also other brain regions such as the cerebellum (CB), nucleus accumbens, hypothalamus and prefrontal cortex. Consistently, transcriptomics analysis confirmed unaltered imprinting expression in the aged HCP. An exception are three novel non-coding transcripts (B230209E15Rik, Ube2nl and A330076H08Rik) at the Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinted locus which lose strict monoallelic expression during aging. Like imprinting, X-chromosome inactivation was remarkably stable with no signs of aging-driven skewing or relaxation of monoallelic expression of X-linked genes. Our study provides a valuable resource for evaluating monoallelic expression in the aging brain and reveals that, despite epigenetic drift during aging, genomic imprinting and X-chromosome inactivation remain predominantly stable throughout the process of physiological aging in the mouse brain.

molecular biology↗

bioRxiv2020

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. These analyses allow the identification of long-range cis-regulatory circuits, including a novel super-enhancer of the Hoxa locus, as well as larger and more detailed gene-regulatory networks, whose importance we demonstrate through perturbation of network members.

cancer biology↗

bioRxiv2019

Genetic modification of primary human B cells generates translationally-relevant models of high-grade lymphoma

Sequencing studies of Diffuse Large B Cell Lymphoma (DLBCL) have identified hundreds of recurrently altered genes. However, it remains largely unknown whether and how these mutations may contribute to lymphomagenesis, either individually or in combination. Existing strategies to address this problem predominantly utilize cell lines, which are limited by their initial characteristics and subsequent adaptions to prolonged in vitro culture. Here, we describe a novel co-culture system that enables the ex vivo expansion and viral transduction of primary human germinal center B cells. The incorporation of CRISPR/Cas9 technology enables high-throughput functional interrogation of genes recurrently mutated in DLBCL. Using a backbone of BCL2 with either BCL6 or MYC we have identified co-operating oncogenes that promote growth and survival, or even full transformation into synthetically engineered models of DLBCL. The resulting tumors can be expanded and sequentially transplanted in vivo, providing a scalable platform to test putative cancer genes and for the creation of mutation-directed, bespoke lymphoma models.

cancer biology↗