Biology subjects

Mayorek, N.

Publications and source records attributed to Mayorek, N..

4 recordsLinked to original sources

bioRxiv2026

Stage-specific metabolic rewiring coordinates nucleotide supply and demand during spermatogenesis

Male meiotic prophase I features a major transition from leptotene/zygotene to pachytene/diplotene characterized by a massive transcriptomic and proteomic shift, yet how metabolism is coordinated across this transition remains unclear. Here, using stage-resolved purification of spermatogenic cells combined with respirometry, proteomics, metabolomics, and isotope tracing, we define metabolic programs across these stages. Early prophase cells rely on glutamine and fatty acid {beta}-oxidation to sustain mitochondrial respiration while directing glucose into the pentose phosphate pathway and de novo pyrimidine synthesis. In contrast, late prophase cells utilize glucose and lactate as fuels, suppress fatty-acid oxidation, lose pentose phosphate pathway entry, and silence nucleotide biosynthesis despite a surge in nascent RNA synthesis and lower nucleotide pools. Inhibiting nucleoside uptake does not impair meiotic progression, indicating that late prophase transcription depends primarily on nucleotide pools synthesized earlier. These findings reveal a developmentally programmed separation between nucleotide production in early prophase and nucleotide use in later meiotic stages. TEASERMeiotic germ cells rewire central carbon metabolism to match stage-specific nucleotide production and RNA demand during spermatogenesis.

developmental biology↗

bioRxiv2025

Dynamic Ribosomal RNA Methylation Regulates Translation in the Hematopoietic System and is Essential for Stem Cell Fitness

Self-renewal and differentiation are at the basis of hematopoiesis. While it is known that tight regulation of translation is vital for hematopoietic stem cells (HSCs) biology, the mechanisms underlying translation regulation across the hematopoietic system remain obscure. Here we reveal a novel mechanism of translation regulation in the hematopoietic hierarchy, which is mediated by ribosomal RNA (rRNA) methylation dynamics. Using ultra-low input ribosome-profiling, we characterized cell-type-specific translation capacity during erythroid differentiation. We found that translation efficiency changes progressively with differentiation and can distinguish between discrete cell populations as well as to define differentiation trajectories. To reveal the underlying mechanism, we performed comprehensive mapping of the most abundant rRNA modification - 2-O-methyl (2OMe). We found that, like translation efficiency, 2OMe dynamics followed a distinct trajectory during erythroid differentiation. Genetic perturbation of individual 2OMe sites demonstrated their distinct roles in modulating proliferation and differentiation. By combining CRISPR screening, molecular and functional analyses, we identified a specific methylation site, 28S-Gm4588, which is progressively lost during differentiation, as a key regulator of HSC self-renewal. We showed that low methylation at this site led to translational skewing, mediated mainly by codon frequency, which promoted differentiation. Functionally, HSCs with diminished 28S-Gm4588 methylation exhibited impaired self-renewal capacity ex-vivo, and loss of fitness in-vivo in bone marrow transplantations. Extending our findings beyond the hematopoietic system, we also found distinct dynamics of 2OMe profiles during differentiation of non-hematopoietic stem cells. Our findings reveal rRNA methylation dynamics as a general mechanism for cell-type-specific translation, required for cell function and differentiation. KEY POINTSO_LIHematopoietic differentiation is associated with rRNA methylation dynamics to control cell-type-specific translation. C_LIO_LITranslation efficiency can distinguish discrete cell types and define differentiation trajectories. C_LIO_LIHSC fitness is regulated by a single rRNA methylation. C_LI

molecular biology↗

bioRxiv2022

2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline

2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and some transient biological processes. Of all organs, the testis harbors the highest baseline physiological levels of 2HG, yet its putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of spermatogenesis by the testis specific lactate dehydrogenase C (LDHC), beginning at the last stages of prophase I. Unexpectedly LDHC enters nuclei and concentrates in centromeres. LDHC-generated L-2HG controls centromere condensation and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. These effects are rapid and specific to L but not D-2HG. In vivo depletion of L-2HG causes centromere malfunction and activation of the spindle assembly checkpoint. Our findings reveal that 2HG can directly affect centromere and pericentromeric heterochromatin conformation and function and is necessary for licensing chromosome segregation.

cell biology↗

bioRxiv2018

Germline DNA replication timing shapes mammalian genome composition

Mammalian DNA is replicated in a highly organized and regulated manner. Large, Mb-sized regions are replicated at defined times along S phase. DNA Replication Timing (RT) has been suggested to play an important role in shaping the mammalian genome by affecting mutation rates. Previous analyses relied on somatic DNA RT profiles, while to fully understand the influences of RT on the mammalian genome, germ cell RT information is necessary, as only germline mutations are passed to offspring and thus affect genomic composition. Using an improved RT mapping technique that allows mapping the RT from limited amounts of cells, we measured RT from two stages in the mouse germline - primordial germ cells (PGCs) and spermatogonial stem cells (SSCs). The germ cell RT profiles were distinct from those of both somatic and embryonic tissues. The correlations between RT and both mutation rate and recombination hotspots were not only confirmed in the germline tissues, but were shown to be stronger compared to correlations with RT of somatic tissues, emphasizing the importance of using RT profiles from the correct tissue of origin. Expanding the analysis to additional genetic features such as GC content, transposable elements (SINEs and LINEs) and gene density, also revealed a stronger correlation with the germ cell RT maps. GC content stratification along with multiple regression analysis revealed the independent contribution of RT to SINE, gene, mutation and recombination hotspot densities. Taken together, our results point to the centrality of RT in shaping multiple levels of mammalian genome composition.

genomics↗