Biology subjects

Telerman, S. B.

Publications and source records attributed to Telerman, S. B..

2 recordsLinked to original sources

bioRxiv2023

Post-translational regulation of the Numb/Notch pathway in neurogenesis and cancer by Dlk2

Perturbations in fundamental developmental pathways have a profound influence on tumorigenesis. Numb plays a pivotal role in vertebrate development, including neurogenesis and is a key negative regulator of Notch signaling1, 2. Perturbation of Numb expression affects brain morphology and cell fate3. While extensive research has been conducted on canonical Notch ligands, regulation by vertebrate-specific non-canonical ligands is not understood. Here we identify Delta like non-canonical Notch ligand 2/EGFL9 (Dlk2) as a regulator of zebrafish neurogenesis with mutants exhibiting early increase and subsequent depletion of neural stem cells, decreased radial glial cells density, impaired neuronal cell distribution, and hypersensitivity to stimuli mimicking the embryonic murine Numb/Numblike null phenotype3. Numb function is inactivated by aberrant phosphorylation4, and we show that Dlk2 protein exhibits a high affinity direct interaction with Numb, with loss of Dlk2 in zebrafish telencephalon increasing Numb Ser276 phosphorylation with a concomitant increase in Notch signaling. Patients with tumors exhibiting reduced levels of Dlk2 have a poorer prognosis, while overexpression of Dlk2 in human cancer cell lines reduces cell proliferation. Our findings identify Dlk2 as a key partner of Numb, a gatekeeper of its activity, and an important player in a network of protein interactions regulating both neurogenesis and cancer with potential therapeutic implications.

cell biology↗

bioRxiv2022

Weak parent-of-origin expression bias: is this imprinting?

In mouse and human, genes subjected to genomic imprinting have been shown to function in development, behaviour, and post-natal adaptations. Failure to correctly imprint genes in human is associated with developmental syndromes, adaptive and metabolic disorders during life as well as numerous forms of cancer. In recent years researchers have turned to RNA-seq technologies applied to reciprocal hybrid strains of mice to identify novel imprinted genes, causing a 3-fold increase in genes reported as having a parental origin specific expression bias. The functional relevance of parental origin-specific expression bias is not fully appreciated especially since many are reported with only minimal parental bias (e.g. 51:49). Here we present an in-depth meta-analysis of previously generated RNA-seq data and show that the methods used to generate and analyse libraries greatly influence the calling of allele-specific expression. Validation experiments show that most novel genes called with parental-origin specific allelic bias are artefactual, with the mouse strain contributing a larger effect on expression biases than parental origin. Of the weak novel genes that do validate, most are located at the periphery of known imprinted domains, suggesting they may be affected by local allele- and tissue-specific conformation. Together these findings highlight the need for robust tools, definitions, and validation of putative imprinted genes to provide meaningful information within imprinting databases and to understand the functional and mechanistic implications of the process.

genomics↗