Biology subjects

Hunter, N.

Publications and source records attributed to Hunter, N..

25 records · Page 2Linked to original sources

bioRxiv2019

GENOMIC COMPETITION FOR NOISE REDUCTION SHAPED EVOLUTIONARY LANDSCAPE OF MIR-4673

The genomic platform that informs evolution of microRNA cascades remains unknown. Here we capitalized on the recent evolutionary trajectory of hominin-specific miRNA-4673 (Dokumcu et al., 2018) encoded in intron 4 of notch-1 to uncover the identity of one such precursor genomic element and the selective forces acting upon it. The miRNA targets genes that regulate Wnt/{beta}-catenin signalling cascade. Primary sequence of the microRNA and its target region in Wnt modulating genes evolved from homologous signatures mapped to homotypic cis-clusters recognised by TCF3/4 and TFAP2A/B/C families. Integration of homologous TFAP2A/B/C cis-clusters (short range inhibitor of {beta}-catenin (Li and Dashwood, 2004)) into the transcriptional landscape of Wnt cascade genes can reduce noise in gene expression (Blake et al., 2003). Probabilistic adoption of miRNA secondary structure by one such cis-signature in notch-1 reflected selection for superhelical curvature symmetry of precursor DNA to localize a nucleosome that overlapped the latter cis-cluster. By replicating the cis-cluster signature, non-random interactions of the miRNA with key Wnt modulator genes expanded the transcriptional noise buffering capacity via a coherent feed-forward loop mechanism (Hornstein and Shomron, 2006). In consequence, an autonomous transcriptional noise dampener (the cis-cluster/nucleosome) evolved into a post-transcriptional one (the miRNA). The findings suggest a latent potential for remodelling of transcriptional landscape by miRNAs that capitalize on non-random distribution of genomic cis-signatures.

systems biology↗

bioRxiv2019

Engineering recombination between diverged yeast species reveals genetic incompatibilities

The major cause of the sterility of F1 hybrids formed between Saccharomyces cerevisiae and Saccharomyces paradoxus is anti-recombination. The failure of homologous chromosomes from the different species to recombine causes them to mis-segregate, resulting in aneuploid gametes, most of which are inviable. These effects of anti-recombination have previously impeded the search for other forms of incompatibility, such as negative genetic interactions (Bateson-Dobzhoansky-Muller incompatibilities). By suppressing the meiotic expression of MSH2 and SGS1, we could increase recombination and improve hybrid fertility seventy-fold. This allowed us to recover meiotic tetrads in which all four gametes were viable, ensuring that segregation had occurred properly to produce perfectly haploid, not aneuploid, recombinant hybrid gametes. We sequenced the genomes of 84 such tetrads, and discovered that some combinations of alleles from different species were significantly under-represented, indicating that there are incompatible genes contributing to reproductive isolation.

evolutionary biology↗

bioRxiv2019

A pseudo-meiotic centrosomal function of TEX12 in cancer

Cell division by meiosis involves an extraordinary chromosome choreography including pairing, synapsis and crossing over between homologous chromosomes1, 2. The many meiosis-specific genes involved in these processes also constitute a latent toolbox of chromosome remodelling and recombination factors that may be exploited through aberrant expression in cancer3, 4. Here, we report that TEX12, a structural protein involved in meiotic chromosome synapsis5-7, is aberrantly expressed in human cancers, with high TEX12 levels correlating with poor prognosis. We find that TEX12 knock-down causes proliferative failure in multiple cancer cell lines, and confirm its role in the early stages of oncogenesis through murine cancer models. Remarkably, somatically expressed TEX12 localises to centrosomes, leading to altered centrosome number and structure, features associated with cancer development. Further, we identify TEX12 in meiotic centrin-rich bodies, likely precursors of the mitotic centrosome, suggesting that this may represent an additional cellular function of TEX12 in meiosis that has been previously overlooked. Thus, we propose that an otherwise meiotic function of TEX12 in centrosome duplication is responsible for promoting oncogenesis and cellular proliferation in cancer, which may be targeted for novel cancer therapeutics and diagnostics.

cell biology↗

bioRxiv2018

Maternal Obesity Enhances Oocyte Chromosome Abnormalities Associated With Aging

Obesity is increasing globally and maternal obesity has adverse effects on pregnancy outcomes and the long-term health of offspring. Maternal obesity has been associated with pregnancy failure through impaired oogenesis and embryogenesis. However, whether maternal obesity causes chromosome abnormalities in oocytes has remained unclear. Here we show that chromosome abnormalities are increased in the oocytes of obese mice and identify weakened sister-chromatid cohesion as the likely cause. Numbers of full-grown follicles retrieved from obese mice were the same as controls and the efficiency of in vitro oocyte maturation remained high. However, chromosome abnormalities presenting in both metaphase-I and metaphase-II were elevated, most prominently the premature separation of sister chromatids. Weakened sister-chromatid cohesion in oocytes from obese mice was manifested both as the terminalization of chiasmata in metaphase-I and as increased separation of sister centromeres in metaphase II. Obesity-associated abnormalities were elevated in older mice implying that maternal obesity exacerbates the deterioration of cohesion seen with advancing age.

genetics↗

bioRxiv2018

The crossover function of MutSγ is activated via Cdc7-dependent stabilization of Msh4

The MutS{gamma} complex, Msh4-Msh5, binds DNA joint-molecule (JM) intermediates during homologous recombination to promote crossing over and accurate chromosome segregation at the first division of meiosis. MutS{gamma} facilitates the formation and biased resolution of crossover-specific JM intermediates called double Holliday junctions. Here we show that these activities are governed by regulated proteasomal degradation. MutS{gamma} is initially inactive for crossing over due to an N-terminal degron on Msh4 that renders it unstable. Activation of MutS{gamma} requires the Dbf4-dependent kinase, Cdc7 (DDK), which directly phosphorylates and thereby neutralizes the Msh4 degron. Phosphorylated Msh4 is chromatin bound and requires DNA strand exchange and chromosome synapsis, implying that DDK specifically targets MutS{gamma} that has already bound nascent JMs. Our study establishes regulated protein degradation as a fundamental mechanism underlying meiotic crossover control.

genetics↗

bioRxiv2018

Impeding DNA Break Repair Enables Oocyte Quality Control

Oocyte quality control culls eggs with defects in meiosis. In mouse, oocyte death is triggered by defects in chromosome synapsis and recombination, which involve repair of programmed DNA double-strand breaks (DSBs) between homologous chromosomes. We show that RNF212, a SUMO ligase required for crossing over, also mediates oocyte quality control. Both physiological apoptosis and wholesale oocytes elimination in meiotic mutants require RNF212. RNF212 sensitizes cells to DSB-induced apoptosis within a narrow window when chromosomes desynapse during the transition into quiescence. Analysis of DNA damage during this transition implies that RNF212 impedes DSB repair. Consistently, RNF212 is required for HORMAD1, a negative regulator of inter-sister recombination, to associate with desynapsing chromosomes. We infer that oocytes impede repair of residual DSBs to retain a \"memory\" of meiotic defects that enables quality control processes. These results define the logic of oocyte quality control and suggest RNF212 variants may influence transmission of defective genomes.

genetics↗

bioRxiv2016

A SUMO-Ubiquitin Relay Recruits Proteasomes to Chromosome Axes to Regulate Meiotic Recombination

Meiosis produces haploid gametes through a succession of chromosomal events including pairing, synapsis and recombination. Mechanisms that orchestrate these events remain poorly understood. We found that the SUMO-modification and ubiquitin-proteasomes systems regulate the major events of meiotic prophase in mouse. Interdependent localization of SUMO, ubiquitin and proteasomes along chromosome axes was mediated largely by RNF212 and HEI10, two E3 ligases that are also essential for crossover recombination. RNF212-dependent SUMO conjugation effected a checkpoint-like process that stalls recombination by rendering the turnover of a subset of recombination factors dependent on HEI10-mediated ubiquitylation. We propose that SUMO conjugation establishes a precondition for designating crossover sites via selective protein stabilization. Thus, meiotic chromosome axes are hubs for regulated proteolysis via SUMO-dependent control of the ubiquitin-proteasome system.\n\nOne Sentence SummaryChromosomal events of meiotic prophase in mouse are regulated by proteasome-dependent protein degradation.

genetics↗