Biology subjects

Aktary, Z.

Publications and source records attributed to Aktary, Z..

5 recordsLinked to original sources

bioRxiv2026

BRN2 preserves the melanocyte lineage following ionizing radiation

Adult stem cells maintain tissue homeostasis, but mechanisms preserving their integrity under stress remain incompletely understood. Here, we identify BRN2 (POU3F2), previously implicated in neuronal development, reprogramming of fibroblasts to neurons and in melanoma proliferation, migration and DNA-damage responses, as a key guardian of melanocyte stem cells. Remarkably, we reveal that while Brn2-deficient mice maintain their McSC compartment and normal pigmentation for up to 95 weeks, in contrast, rapid, dose-dependent, permanent hair depigmentation associated with the disappearance of detectable McSCs and differentiated melanocytes occurs in Brn2 KO mice exposed to ionizing radiation but not in WT mice. Importantly, our results indicate that in human follicular melanocytes BRN2 activity in melanocyte stem cells (McSCs) declines with age and that Brn2 promotes melanocyte stem cell regeneration by restraining stress-induced melanocytic differentiation. Our findings establish a previously unrecognized in vivo requirement for BRN2 in preserving the integrity of the melanocyte lineage following ionizing radiation, revealing a stress-dependent function distinct from its largely dispensable role in steady-state McSC maintenance.

cell biology↗

bioRxiv2024

G-quadruplexes in Haloferax volcanii

Archaea, a domain of microorganisms found in diverse environments including the human microbiome, represent the closest known prokaryotic relatives of eukaryotes. This phylogenetic proximity positions them as a relevant model for investigating the evolutionary origins of nucleic acid secondary structures such as G-quadruplexes (G4s), which play regulatory roles in transcription and replication. Although G4s have been extensively studied in eukaryotes, their presence and function in archaea remain poorly characterized. In this study, a genome-wide analysis of the halophilic archaeon Haloferax volcanii identified over 5, 800 potential G4-forming sequences. Biophysical validation confirmed that many of these sequences adopt stable G4 conformations in vitro. Using G4-specific detection tools and super-resolution microscopy, G4 structures were visualized in vivo in both DNA and RNA across multiple growth phases. Comparable findings were observed in the thermophilic archaeon Thermococcus barophilus. Functional analysis using helicase-deficient H. volcanii strains further identified candidate enzymes involved in G4 resolution. These results establish H. volcanii as a tractable archaeal model for G4 biology.

molecular biology↗

bioRxiv2022

The E-cadherin-ESR1-GRPR axis defines a sex-specific metastatic pathway in melanoma

Although tremendous progress has been made in understanding the mechanisms leading to cancer, those governing metastases are still poorly understood. E-cadherin (Ecad) is a cell-cell adhesion molecule essential for tissue homeostasis, and its loss often correlates with the dissemination of human cancers. However, whether and how the loss of Ecad triggers the full metastatic program is largely unknown. Here, we show that the loss of Ecad promotes melanoma lung metastases in females. The loss of Ecad, after the induction of estrogen receptor (ER) expression, activates gastrin-releasing peptide receptor (GRPR) expression. GRPR promotes cellular processes essential for metastasis formation through G{square}q and YAP1 signaling and its pharmacological inhibition reduces metastasis in vivo. This study reveals an Ecad-ER-GRPR metastatic sex dimorphism axis in melanoma that is conserved in human breast cancer and provides proof of concept that the G-coupled receptor GRPR is a therapeutic target for metastasis.

cancer biology↗

bioRxiv2021

Dynlt3, a novel fundamental regulator of melanosome movement, distribution, maturation and transfer

Skin pigmentation is dependent on cellular processes including melanosome biogenesis, transport, maturation and transfer to keratinocytes. However, how the cells finely control these processes in space and time to ensure proper pigmentation remains unclear. Here, we show that a component of the cytoplasmic dynein complex, Dynlt3, is required for efficient melanosome transport, maturation and transfer. In melanocytes with decreased levels of Dynlt3, pigmented melanosomes undergo a more directional (convective) motion leading to their peripheral location in the cell, and are not fully matured. Stage IV melanosomes are more acidic, but still heavily pigmented, resulting in a less efficient melanosome transfer. Finally, the level of Dynlt3 is dependent on {beta}-catenin activity, revealing a novel function of the Wnt/{beta}-catenin signalling pathway during melanocyte and skin pigmentation, by coupling the transport, position and maturation of melanosomes required for their transfer.

cell biology↗

bioRxiv2021

BRN2 is a non-canonical melanoma tumor-suppressor

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, we show that BRN2 haplo-insufficiency is sufficient to promote melanoma initiation and metastasis, acting as a non-canonical tumor suppressor. Mechanistically, BRN2 directly modulates PTEN expression, and PI3K signaling, to drive tumor initiation and progression. Collectively our results reveal that somatic deletion of one BRN2 allele elicits melanoma initiation and progression. SIGNIFICANCEHere, we report frequent mono-allelic loss of the transcription factor BRN2 in human cutaneous melanoma metastases. We developed a mouse model for Brn2-deficient melanoma based on the most common alterations (BrafV600E and Pten loss) in human melanoma and established the role of Brn2 as a functional regulator of tumor initiation, tumor growth, and the formation of metastases in vivo. Mechanistically, BRN2 loss increases PI3K-signaling through PTEN repression, either via MITF induction or not. Overall, we describe a novel tumor suppressor of high prevalence in human melanoma that regulates several steps of in vivo melanomagenesis through two previously unknown molecular mechanisms.

cancer biology↗