The fate of notch-1 transcript is linked to cell cycle dynamics by activity of a natural antisense transcript

Abstract

A core imprint of metazoan life is that perturbations of cell cycle are offset by compensatory changes in successive cellular generations. This trait enhances robustness of multicellular growth and requires transmission of signaling cues within a cell lineage. Notably, the identity and mode of activity of transgenerational signals remain largely unknown. Here we report the discovery of a natural antisense transcript encoded in exon 25 of notch-1 locus (nAS25) by which mother cells control the fate of notch-1 transcript in daughter cells to buffer against perturbations of cell cycle. The antisense transcript is transcribed at G1 phase of cell cycle from a bi-directional E2F1-dependent promoter in the mother cell where the titer of nAS25 is calibrated to the length of G1. Transmission of the antisense transcript from mother to daughter cells stabilizes notch-1 sense transcript in G0 phase of daughter cells by masking it from RNA editing and resultant nonsense-mediated degradation. In consequence, nAS25-mediated amplification of notch-1 signaling reprograms G1 phase in daughter cells to compensate for the altered dynamics of the mother cell. The function of nAS25/notch-1 in integrating G1 phase history of the mother cell into that of daughter cells is compatible with the predicted activity of a molecular oscillator, slower than cyclins, that coordinates cell cycle within cell lineage.

Notch ankyrin domain: evolutionary rise of a thermodynamic sensor

“…We recently reported that transcription from human notch-1 locus is regulated by generation of a cis -natural antisense transcript that restricts the active transcriptional window to G0/early G1 phase of cell cycle [ 12 ]. The antisense transcript also regulates the availability of notch-1 transcript at G1 phase of cell cycle by calibrating RNA editing of the transcript and its subsequent degradation by nonsense-mediated decay [ 12 ].…”

“…We recently reported that transcription from human notch-1 locus is regulated by generation of a cis -natural antisense transcript that restricts the active transcriptional window to G0/early G1 phase of cell cycle [ 12 ]. The antisense transcript also regulates the availability of notch-1 transcript at G1 phase of cell cycle by calibrating RNA editing of the transcript and its subsequent degradation by nonsense-mediated decay [ 12 ]. The critical role of mRNA titre in determining Notch signalling output [ 12 ] is foreshadowed by the evolution of multiple parallel mechanisms that enhance the fidelity of notch transcriptional landscape [ 13 , 14 ].…”

“…The antisense transcript also regulates the availability of notch-1 transcript at G1 phase of cell cycle by calibrating RNA editing of the transcript and its subsequent degradation by nonsense-mediated decay [ 12 ]. The critical role of mRNA titre in determining Notch signalling output [ 12 ] is foreshadowed by the evolution of multiple parallel mechanisms that enhance the fidelity of notch transcriptional landscape [ 13 , 14 ]. While knowledge of the Notch signalling cascade has grown extensively over the past decade [ 4 ], one major question remains unanswered; that is the mechanism(s) that regulate termination of Notch/RBPJ signalling output by triggering dissociation of the active transcriptional complex.…”

Cellular self‐organization: An overdrive in Cambrian diversity?

“…In cellular self‐organization, interactions between individual cells are necessary and sufficient for the emergence of morphogenic landscape. [ 23 ] While there is some evidence that the life cycle history of a mother cell is integrated into that of daughter cells, [ 48 ] the decisions are predominantly memory‐less and based on real‐time interactions of cycling cells with other surrounding cells. In consequence, fate dichotomies such as division/differentiation and sub‐lineage fate adoption are resolved in a coordinated manner according to the outcomes adopted by neighboring cells.…”

“…[ 53 ] The mature miRNA induces autophagy by inhibition of cdk‐18 (human homologue of Pho85) with resultant expansion of G0 phase of cell cycle and shortening of G1 phase. Expansion of G0 leads to amplified degradation of Notch‐1, [ 48 ] a key antagonist of β‐catenin. [ 77 ] In consequence, the coupling activity of β‐catenin is amplified [ 53 ] that in turn triggers an altered self‐organization signature of dividing human neural progenitors.…”