Biology subjects

Moscatelli, M.

Publications and source records attributed to Moscatelli, M..

3 recordsLinked to original sources

bioRxiv2023

XIST dampens X chromosome activity in a SPEN-dependent manner during early human development

XIST long non-coding RNA is responsible for X chromosome inactivation (XCI) in placental mammals, yet it accumulates on both X chromosomes in human female pre-implantation embryos without triggering X chromosome silencing. The long non-coding RNA XACT co-accumulates with XIST on active Xs and may antagonize XIST function. Here we used human ES cells in a naive state of pluripotency to assess the function of XIST and XACT in shaping the X chromosome chromatin and transcriptional landscapes during pre-implantation development. We show that XIST triggers the deposition of polycomb-mediated repressive histone modifications and attenuates transcription of most X-linked genes in a SPEN-dependent manner, while XACT deficiency does not significantly affect XIST activity or X-linked gene expression. Our study demonstrates that XIST is functional prior to XCI, confirms the existence of a transient process of X chromosome dosage compensation, and reveals that X chromosome inactivation and dampening rely on the same set of factors.

molecular biology↗

bioRxiv2022

scMuffin: an R package for resolving solid tumor heterogeneity from single-cell expression data

INTRODUCTIONSingle-cell (SC) gene expression analysis is crucial to dissect the complex cellular heterogeneity of solid tumors, which is one of the main obstacles for the development of effective cancer treatments. Such tumors typically contain a mixture of cells with aberrant genomic and transcriptomic profiles affecting specific sub-populations that might have a pivotal role in cancer progression, whose identification eludes bulk RNA-sequencing approaches. We presentscMuffin, an R package that enables the characterization of cell identity in solid tumors on the basis of a various and complementary analyses on SC gene expression data. RESULTSscMuffin provides a series of functions to calculate qualitative and quantitative scores, such as: expression of marker sets for normal and tumor conditions, pathway activity, cell state trajectories, CNVs, transcriptional complexity and proliferation state. Thus, scMuffin facilitates the combination of various evidences that can be used to distinguish normal and tumoral cells, define cell identities, cluster cells in different ways, link genomic aberrations to phenotypes and identify subtle differences between cell subtypes or cell states. We analysed public SC expression datasets of human high-grade gliomas as a proof-of-concept to show the value of scMuffin and illustrate its user interface. Nevertheless, these analyses lead to interesting findings, which suggest that some chromosomal amplifications might underlie the invasive tumor phenotype and the presence of cells that possess tumor initiating cells characteristics. CONCLUSIONSThe analyses offered by scMuffin and the results achieved in the case study show that our tool helps addressing the main challenges in the bioinformatics analysis of SC expression data from solid tumors.

bioinformatics↗

bioRxiv2019

A primate-specific retroviral enhancer wires the XACT lncRNA into the core pluripotency network in human

Transposable elements (TEs) have been of paramount importance in shaping genomic and epigenomic landscapes of their hosts and in driving the expansion of gene regulatory networks during mammalian evolution. They are found in nearly all long non-coding RNAs (lncRNAs) and have promoted their evolution and function, often in a species- and tissue-specific manner. X-chromosome inactivation (XCI) is an essential process that relies on several TE-enriched lncRNAs. While XCI is conserved across species, one striking difference between human and mouse is the existence of XACT (X active coating transcript), a human-specific lncRNA that coats active X chromosomes in pluripotent cells and may oppose X chromosome silencing in this context. Here, we explore how different families of TEs have contributed to shaping the XACT locus and how they couple its expression to pluripotency in humans. Through a combination of sequence analysis across primates, transcriptional interference and genome editing in human embryonic stem cells (hESCs), we identify a critical enhancer for the transcriptional regulation of the XACT locus that evolved from an ancestral group (LTR48B/ERV1) of mammalian endogenous retroviruses (ERVs), prior to the emergence of XACT. Furthermore, we show that this ancient ERV was hijacked by evolutionarily younger hominoid-specific ERVs that gave rise to the promoter of XACT, thus wiring its expression to the pluripotency network. This work illustrates how retroviral-derived sequences may intervene in species-specific regulatory pathways.

molecular biology↗