Biology subjects

Herbert, M.

Publications and source records attributed to Herbert, M..

6 recordsLinked to original sources

bioRxiv2026

Defective HIRA driven chromatin maintenance underlies age related decline in oocyte quality

The rapid fertility decline in women over 35 years of age has been attributed to decreasing oocyte quality. Aging oocytes accumulate DNA damage, chromosome segregation defects and altered epigenetic modifications. Critically, the molecular mechanisms underlying these changes remain poorly understood. Here we uncovered that in the mouse, the HIRA driven H3.3 histone replacement is attenuated during oocyte aging leading to the loss of chromatin homeostasis. The loss of HIRA function is caused by its SUMOylation resulting in the disruption of HIRA-UBN1-CABIN1 complex and its association with chromatin. We further show that preventing HIRA SUMOylation restores H3.3 incorporation and chromatin integrity in aged mouse oocytes leading to improved oocyte maturation and preimplantation development rates. Importantly, similar chromatin homeostasis defect is observed in aging human oocytes pointing towards a conserved process. Our findings provide novel insights into the molecular mechanisms underlying age-related oocyte quality decline and pave the way for clinical interventions.

developmental biology↗

bioRxiv2026

Spatial atlas of the ovary identifies molecular events in primordial follicle activation in humans

The human ovarian reserve is established prenatally, when granulosa cells encapsulate germ cells to form a pool of quiescent primordial follicles, that ultimately determines the female reproductive and endocrine lifespan. From birth to menopause, subsets of these quiescent follicles, located in the thin outer ovarian cortex, are activated and undergo a growth programme with progressive inward migration to the inner cortex, before either undergoing atresia or, during reproductive age, ovulation. Disruption of this process may lead to infertility, metabolic disorders and early menopause, yet early follicle development remains largely poorly understood. Here, we generate the most comprehensive single-cell and spatial multiomics atlas of the human pre- and postnatal ovarian cortex, integrating transcriptomic and chromatin profiles from over four million cells obtained from fetal and newly profiled pediatric and adult donors. We resolve the early granulosa cell trajectory at unprecedented resolution and identify a retinoic acid-associated regulatory switch accompanying follicle activation. We further show that stromal fibroblasts are not homogeneous, but instead form a dynamic scaffold establishing previously unrecognised morphogen and paracrine gradients that organise the cortex into functional niches supporting quiescent, growing, and atretic follicles. Finally, we identify ovarian lipid associated macrophages (oLAMs) that localise around follicles and are likely to support tissue remodelling during folliculogenesis. Together, this atlas provides a foundational blueprint for human ovarian development and homeostasis, and provides a framework for improving strategies in fertility preservation and in vitro follicle maturation.

cell biology↗

bioRxiv2024

Identification of a specific granular marker of zebrafish eosinophils enables development of new tools for their study

Eosinophils control many aspects of the vertebrate innate immune response. They contribute to homeostasis, inflammatory conditions and defense against pathogens, yet, their function in disease often remains enigmatic. The zebrafish has emerged as a useful model organism for human diseases but tools to study eosinophils in this model are severely limited. Here, we characterize a new and highly specific marker for eosinophils in zebrafish and report a new transgenic reporter line to visualize eosinophils in vivo. In addition, we created a polyclonal antibody that allows the identification of eosinophils ex vivo. These new tools expand the toolkit to study eosinophils in the zebrafish model. Using our tools, we have been able to identify the likely ortholog of eosinophil major basic protein, a critical mediator of eosinophil function, in zebrafish. These advances will allow for the investigation of eosinophil biology in the zebrafish model organism, allowing researchers to identify the contribution of eosinophils to the many diseases that are modeled within zebrafish and also shed light on the evolution of eosinophils within vertebrates.

immunology↗

bioRxiv2024

Suppression of ERK signalling promotes pluripotent epiblast in the human blastocyst

Studies in the mouse demonstrate the importance of fibroblast growth factor (FGF) and extra-cellular receptor tyrosine kinase (ERK) in specification of embryo-fated epiblast and yolk-sac-fated hypoblast cells from uncommitted inner cell mass (ICM) cells prior to implantation. Molecular mechanisms regulating specification of early lineages in human development are comparatively unclear. Here we show that exogenous FGF stimulation leads to expanded hypoblast molecular marker expression, at the expense of the epiblast. Conversely, we show that specifically inhibiting ERK activity leads to expansion of epiblast cells functionally capable of giving rise to naive human pluripotent stem cells. Single-cell transcriptomic analysis indicates that these epiblast cells downregulate FGF signalling and upregulate molecular markers associated with naive pluripotency. Our functional study demonstrates for the first time the molecular mechanisms governing ICM specification in human development, whereby segregation of the epiblast and hypoblast lineages occurs during maturation of the mammalian embryo in an ERK signal-dependent manner.

developmental biology↗

bioRxiv2022

Mixed Models Quantify Annual Volume Change; Linear Regression Determines Thalamic Volume as the Best Subcortical Structure Volume Predictor in Alzheimer's Disease and Aging

BackgroundThalamus-hippocampus-putamen and thalamus-cerebellar interconnections are dense. The extent this connectivity is paralleled by each structures volume impact on another is unquantified in Alzheimers disease (AD). Mixed model quantification of annual volume change in AD is scarce and absent inclusive of the cerebellum, hippocampus, putamen and lateral ventricles and thalamus. Among these structures, autopsy evidence of early-stage AD seems largely but not entirely restricted to the hippocampus and thalamus. ObjectiveVariation in annual volume related to time and baseline age was assessed for the hippocampus, putamen, cerebellum, lateral ventricles and thalamus. Which subcortical structures volume had the largest explanatory effect of volume variation in other subcortical structures was also determined. MethodThe intraclass correlation coefficient was used to assess test-retest reliability of structure automated segmentation. Linear regression (N = 45) determined which structures volume most impacted volume of other structures. Finally, mixed models (N = 36; 108 data points) quantified annual structure volume change from baseline to 24-months. ResultsHigh test-retest reliability was indicated by a mean ICC score of .989 (SD = .012). Thalamic volume consistently had the greatest explanatory effect of hippocampal, putamen, cerebellar and lateral ventricular volume. The group variable proxy for AD significantly contributed to the best-fitting hippocampal linear regression model, hippocampal and thalamic longitudinal mixed models, and approached significance in the longitudinal lateral ventricular mixed model. Mixed models determined time (1 year) had a negative effect on hippocampal, cerebellar and thalamic volume, no effect on putamen volume, and a positive effect on lateral ventricular volume. Baseline age had a negative effect on hippocampal and thalamic volume, no effect on cerebellar or putamen volume and a positive effect on lateral ventricular volume. InterpretationLinear regression determined thalamic volume as a virtual centralized index of hippocampal, cerebellar, putamen, and lateral ventricular volume. Relative to linear regression, longitudinal mixed models had greater sensitivity to detect contribution of early AD, or potential AD pathology (MCI), via the group variable not just to volume reduction in the hippocampus but also in the thalamus.

neuroscience↗

bioRxiv2017

Tex19.1 Regulates Acetylated SMC3 Cohesin and Prevents Aneuploidy in Mouse Oocytes

Age-dependent oocyte aneuploidy, a major cause of Down syndrome, is associated with declining sister chromatid cohesion in postnatal oocytes. Here we show that cohesion in postnatal mouse oocytes is regulated by Tex19.1. We show that Tex19.1-/- oocytes have defects in the maintenance of chiasmata, mis-segregate their chromosomes during meiosis, and transmit aneuploidies to the next generation. By reconstituting aspects of this pathway in mitotic somatic cells, we show that Tex19.1 regulates an acetylated SMC3-marked subpopulation of cohesin by inhibiting the activity of the E3 ubiquitin ligase UBR2 towards specific substrates, and that UBR2 itself has a previously undescribed role in negatively regulating acetylated SMC3. Lastly, we show that acetylated SMC3 is associated with meiotic chromosome axes in oocytes, but that this is reduced in the absence of Tex19.1. These findings indicate that Tex19.1 maintains acetylated SMC3 and sister chromatid cohesion in postnatal oocytes, and prevents aneuploidy in the female germline.

genetics↗