Biology subjects

Mercedes, M.

Publications and source records attributed to Mercedes, M..

3 recordsLinked to original sources

bioRxiv2024

H2AK119ub dynamics controls hair follicle stem cell quiescence

The transition of stem cells from a quiescent state to an active state is a finely tuned process that requires the dismantling of the quiescence program and the establishment of a cell cycle-promoting transcriptional landscape. Whether epigenetic processes control stem cell states to promote the regeneration of adult tissues remains elusive. In this study, we show that a repressive histone modification, H2AK119ub, is dynamic between quiescent and active hair follicle stem cells (HFSCs) in the adult murine skin. Ablation of H2AK119ub in HFSCs leads to impaired quiescence leading to premature activation and an eventual exhaustion of HFSC pool. Transcriptional and chromatin studies revealed that H2AK119ub directly represses a proliferation promoting transcriptional program in the HFSCs to preserve quiescence. Lastly, we identify that the inhibitory FGF signaling produced by the hair follicle niche keratinocytes maintains H2AK119ub in quiescent HFSCs. Together, these findings reveal that a repressive histone mark, H2AK119ub, is under the dynamic regulation of inhibitory niche signaling to prevent the untimely establishment of an activated state to preserve SC function and longevity.

cell biology↗

bioRxiv2023

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC lines to express 4R-tau and 4R-tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes, including shared transcriptomic signatures, autophagic body accumulation, and impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.

neuroscience↗

bioRxiv2021

Tau interactome mapping reveals dynamic processes in synapses and mitochondria associated with neurodegenerative disease

Tau (MAPT) drives neuronal dysfunction in Alzheimers disease (AD) and other tauopathies. To dissect the underlying mechanisms, we combined an engineered ascorbic acid peroxidase (APEX) approach with quantitative affinity purification mass spectrometry (AP-MS) followed by proximity ligation assay (PLA) to characterize Tau interactomes modified by neuronal activity and mutations that cause frontotemporal dementia (FTD) in human induced pluripotent stem cell (iPSC)-derived neurons. We established activity-dependent interactions of Tau with presynaptic vesicle proteins during Tau secretion and mapped the exact APEX-tau-induced biotinylated tyrosines to the cytosolic domains of the interacting vesicular proteins. We showed that FTD mutations impair bioenergetics and markedly diminished Taus interaction with mitochondria proteins, which were downregulated in AD brains of multiple cohorts and correlated with disease severity. These multi-modal and dynamic Tau interactomes with unprecedented spatiotemporal resolution shed novel insights into Taus role in neuronal function and disease-related processes with potential therapeutic targets to block Tau-mediated pathogenesis.

neuroscience↗